Garcia-Cazorla Àngels

Mochel Fanny
email: fanny.mochel@upmc.fr

Lamari Foudil
email: foudil.lamari@psl.aphp.fr

Saudubray Jean-Marie

J M Saudubray
email: jmsaudubray@orange.fr

Garcia Cazorla

Fanny Mochel

Foudil Lamari

The clinical spectrum of inherited diseases involved in the synthesis and remodeling of complex lipids. A tentative overview

Keywords: Complex lipids, phospholipids, inborn errors of metabolism, spastic paraplegia, neurodegeneration with brain iron accumulation, peripheral neuropathy, ichthyosis, retinal dystrophy, chondrodysplasia, hepatic steatosis

Over one hundred diseases related to inherited defects of complex lipids synthesis and remodeling are now reported. Most of them were described within the last 5 years. New descriptions and phenotypes are expanding rapidly. While the associated clinical phenotype is currently difficult to outline, with only few patients identified, it appears that all organs and systems may be affected. The main clinical presentations can be divided into (1) Diseases affecting the central and peripheral nervous system.

Complex lipid synthesis disorders produce prominent motor manifestations due to upper and/or lower motoneuron degeneration. Motor signs are often complex, associated with other neurological and extra-neurological signs. Three neurological phenotypes, spastic paraparesis, neurodegeneration with brain iron accumulation and peripheral neuropathies, deserve special attention. Many apparently well clinically defined syndromes are not distinct entities, but rather clusters on a continuous spectrum, like for the PNPLA6-associated diseases, extending from Boucher-Neuhauser syndrome via Gordon Holmes syndrome to spastic ataxia and pure hereditary spastic paraplegia; (2) Muscular/cardiac presentations; (3) Skin symptoms mostly represented by syndromic (neurocutaneous) and non syndromic ichthyosis; (4) Retinal dystrophies with syndromic and non syndromic retinitis pigmentosa, Leber congenital amaurosis, cone rod dystrophy, Stargardt disease; (5) Congenital bone dysplasia and segmental overgrowth disorders with congenital lipomatosis; (6) Liver presentations characterized mainly by transient neonatal cholestatic jaundice and non alcoholic liver steatosis with hypertriglyceridemia; and (7) Renal and Immune presentations. Lipidomics and molecular functional studies could help elucidating the mechanism(s) of dominant versus recessive inheritance observed for the same gene in a growing number of these disorders.

Introduction

The quantitative importance of lipids in the nervous system makes the brain and peripheral nerves a privileged target for defects of complex lipids synthesis and remodeling. However, besides the role of complex lipids in neurological functions and signaling, this review highlighs the importance of these molecules in photoreceptor function, the epidermal water barrier, bone and liver metabolism. This chapter is an attempt to give a clinical overview of this new group of IEM focusing on neurological, muscular, cardiac, ophthalmological, dermatological, orthopedic and hepatic presentations.

Neurological presentations

Both central (CNS) and peripheral nervous systems are frequently involved in complex lipid synthesis and remodeling disorders. Careful grouping of patients in well-defined neurological syndromes is a practical and useful approach for clinicians (Tables 1 and2). However, due to the rapidly growing number of diseases and the expanding phenotype of many of these diseases, this approach needs a constant update. As general messages, we wish to highlight the following points:

-Complex lipid synthesis and remodeling disorders produce prominent motor manifestations due upper and/or lower motoneuron degeneration. In fact, these movement disorders are the most remarkable neurological presentations in this category of diseases. Motor signs are often complex, associated with other neurological and extra-neurological signs.

-These disorders should be considered in patients with cerebral-palsy like phenotype, spastic paraparesis, ataxia, NBIA (neurodegeneration associated with brain iron accumulation) and peripheral neuropathy of unknown origin.

-In general, psychiatric disturbances are rare. They have been described in different NBIA, especially as late-onset manifestations, but they rarely appear in other types of complex lipid biosynthesis disorders.

-Epilepsy is also rare as a prominent sign; however, there are some defects that produce early severe refractory epilepsy.

-Developmental delay (DD) and intellectual disability (ID) are commonly present, as in many other neurometabolic diseases, but in general associated with other neurological and extra-neurological signs as "syndromic mental retardation". These additional signs are often useful to the diagnostic approach. Additionally, one interesting message learnt from these IEM is the inclusion of serum alkaline phosphatase in the metabolic work-up of mental retardation for the detection of GPIanchor-synthesis defects [START_REF] Krawitz | PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome[END_REF]. Three neurological phenotypes, spastic paraparesis, NBIA and peripheral neuropathies, deserve especial attention (Tables 1 and2).

Hereditary spastic paraparesis (HSP) -Table 1 HSP is a heterogeneous group of genetic disorders in which the main feature is progressive spasticity in the lower limbs due to pyramidal tract dysfunction as a result of a 'dying back' degeneration of the cortico-spinal tracts. The critical role of complex lipids in signal transduction and membrane rigidity/fluidity may partly explain how defects in synthesis and remodeling of these lipids often lead to the degeneration of some of the longest, and therefore most vulnerable, axons in the CNS. HSP refers to a syndrome that includes lower extremity weakness and spasticity, each of varying degree, age of onset and progression. There are more than 50 genetic types of HSP, many of them described in the last years [START_REF] Lo Giudice | Hereditary spastic paraplegia: Clinicalgenetic characteristics and evolving molecular mechanisms[END_REF]. They are classified clinically as "pure" or "uncomplicated" and "complex" or "complicated" [START_REF] Harding | Classification of the Hereditary Ataxias and Paraplegias[END_REF]. While some genetic types of HSP usually manifest as "uncomplicated"e.g. SPG4 HSP due to spastin gene mutation, the single most common form of autosomal dominant HSP -, other genetic types usually present as complex HSP syndromes [START_REF] Fink | Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms[END_REF]. In general, HSP due to complex lipid biosynthesis defects are autosomal recessive and complicated forms of HSP.

Cerebellar involvement, axonal neuropathy, ichthyosis and ocular abnormalities are amongst the most commonly associated symptoms, together with abnormal brain MRI, especially thin corpus callosum. Rather "pure" HSP, although not invariably, can be observed in SPG28 due to phospholipase A1 deficiency and mutations in DDHD1 [START_REF] Bouslam | Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28)[END_REF] [START_REF] Liguori | Impairment of brain and muscle energy metabolism detected by magnetic resonance spectroscopy in hereditary spastic paraparesis type 28 patients with DDHD1 mutations[END_REF] as well as SPG56 due to cytochrome P450 hydroxylase deficiency and mutations in CYP2U1 [START_REF] Tesson | Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia[END_REF]. About 13 different genes associated with HSP and defects in lipid biosynthesis and remodeling have been described until now. They participate in different biological functions, especially phospholipid remodelling (PNPLA6, CYP2U1, DDHD1 and DDHD2), fatty acid hydroxylation (CYP2U1) as well as sphingolipids biosynthesis (FA2H, B4GALNT1).

Neurodegeneration with Brain Iron Accumulation (NBIA) -Table 1

NBIA syndromes represent a group of degenerative extrapyramidal monogenic disorders with accumulation of iron in the brain, usually in the basal banglia [START_REF] Gregory | Genetics of neurodegeneration with brain iron accumulation[END_REF]. In general, NBIA cause progressive dystonia, bulbar symptoms and pyramidal signs in young children whereas parkinsonism usually appears later.

Cognitive decline occurs in some subtypes of NBIA, but more often cognition is relatively spared. Cerebellar atrophy is a frequent finding. So far, 10 different genetic forms have been described [START_REF] Levi | Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms[END_REF]. Two forms are linked to mutations in genes directly involved in iron metabolism: neuroferritinopathy (FTL gene) and aceruloplasminemiawhere the ceruloplasmin gene product is defective. In the other forms, the link with iron metabolism is not evident. The biochemical pathways involving lipid metabolism and membrane/organelles (mitochondria) remodeling seem to play an important mechanistic role in NBIA disorders. At least 4 genes, PANK2, PLA2G6, COASY and FA2H, encode proteins involved in lipid metabolism.

The protein encoded by c19orf12 is linked to the mitochondrial outer membrane and is presumably connected with lipid metabolism although it has not been completely characterized yet [START_REF] Hartig | Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation[END_REF].(Tiranti this issue)

Peripheral neuropathies -Table 2 The diagnosis of peripheral neuropathies, rely on clinical and electrophysiological criteria. The general classification depends on whether there is an involvement of large fibersi.e. motor weakness, loss of deep reflexes, muscle atrophy, sensory ataxiaversus small fibersautonomic dysfunction, abnormal temperature sensibility pinprick lossand whether the neuropathy is predominantly demyelinating or axonal. The lipid composition of myelin and transport of lipid-associated myelin proteins contribute to the observed vulnerability of myelin in lipid metabolism disorders [START_REF] Chrast | Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models[END_REF]. Currently, more than 20 genes have been linked to IEM of lipid biosynthesis and remodeling defects. Different subtypes of peripheral neuropathies have been described in these disorders. Most of them are associated with other neurological and extra-neurological sings such as spastic paraparesis, white matter abnormalities, ocular and hearing impairment. However, peripheral neuropathy may be the presenting and/or predominant symptom in some of these diseases. Likewise, diseases of complex lipids biosynthesis and remodeling may present with:

sensory and autonomic neuropathies, especially defects in serine metabolism either with an early onsetthen associated with a global encephalopathyor with an onset during adolescence to adulthoodwith a less severe phenotype (Dick 1993;Rotthier et al. 2012;[START_REF] Murphy | Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2[END_REF][START_REF] Suh | Early-onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation[END_REF][START_REF] Suh | Early-onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation[END_REF].

demyelinating neuropathies, mainly found in peroxisomal defects such as biogenesis defects related to PEX genes, adrenomyeloneuropathy, X-linked adrenoleukodystrophy and Refsum diseasealthough peroxisomal diseases can also manifest with axonal neuropathies axonal neuropathies, often associated with HSP and usually sharing common pathological pathways with HSP.

Muscular and cardiac symptoms -Table 3

Complex lipid synthesis and remodeling disorders may present with the following skeletal and cardiac muscle predominant manifestations:

-Recurrent rhabdomyolysis with myoglobinuria and myalgia. This is a wellrecognized presentation of beta-oxidation defects such as LCHAD and TFP deficiencies [START_REF] Olpin | Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency[END_REF], as well as Lipin-1 deficiency [START_REF] Michot | LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood[END_REF].

These episodes are frequently triggered by catabolic or other stressful situations. A rare peroxisomal defect, racemase deficiency, has been reported as a cause of recurrent rhabdomyolysis in adults [START_REF] Kapina | Relapsing rhabdomyolysis due to peroxisomal alpha-methylacyl-coa racemase deficiency[END_REF].

-Childhood myopathy mimicking congenital dystrophy, with or without heart involvement. Isolated muscle forms include a severe myopathic phenotype at birth due to 3-hydroxyacyl-CoA dehydratase 1 (PTPLA) deficiency [START_REF] Muhammad | Congenital myopathy is caused by mutation of HACD1[END_REF] and the Chanarin-Dorfman syndrome (alpha/beta hydrolase 5 (ABHD5) deficiency). Myopathies with variable cardiac involvement encompass (i) an early onset form with mental retardation and abnormal mitochondrial morphologyi.e.

choline kinase beta (CHKB) deficiency [START_REF] Mitsuhashi | A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis[END_REF], (ii) severe early encephalopathies with seizures and associated signsi.e. defects in dolichol metabolism [START_REF] Lefeber | Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan Omannosylation[END_REF][START_REF] Barone | DPM2-CDG: a muscular dystrophydystroglycanopathy syndrome with severe epilepsy[END_REF]; (iii) Sengers syndrome; and (iv) an adult onset myopathy and cardiomyovasculopathyi.e. neutral lipid storage disease or triglyceride deposit (PNPLA2) [START_REF] Kaneko | A novel mutation in PNPLA2 causes neutral lipid storage disease with myopathy and triglyceride deposit cardiomyovasculopathy: a case report and literature review[END_REF].

-Primary or prominent cardiac presentations revealed by dilated or hypertrophic cardiomyopathy, such as DK1 mutations [START_REF] Kapusta | From discrete dilated cardiomyopathy to successful cardiac transplantation in congenital disorders of glycosylation due to dolichol kinase deficiency (DK1-CDG)[END_REF], Barth syndrome [START_REF] Clarke | Barth syndrome[END_REF] and Sengers syndrome [START_REF] Mayr | Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome[END_REF].

Ophthalmological presentations -

Retinal dystrophiesretinitis pigmentosa, Leber congenital amaurosis, early onset retinal dystrophy and Stargardt disease

There are over four hundred known inherited diseases in which the retina, macula or choroids are substantially involved [START_REF] Rattner | Molecular genetics of human retinal disease[END_REF]Retnet). LCA is a severe retinal dystrophy with infantile onset that presents with profound visual impairment, inability to fixate and nystagmus from birth or within the first few weeks of life. It is the most severe form among the spectrum of these disorders arising within the first few years of life and affecting both rod and cone photoreceptors, also called childhood or early onset retinal dystrophy (EORD) [START_REF] Gu | Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy[END_REF]. [START_REF] Molday | The role of the photoreceptor ABC transporter ABCA4 in lipid transport and Stargardt macular degeneration[END_REF].

Retinitis pigmentosa (RP

Optic nerve degenerationoptic atrophy and glaucoma

Hereditary optic atrophy (OA) is common in neurodegenerative diseases due to IEM, especially white matter diseases and energy deficiencies, and deserves an extensive work-up [START_REF] Saudubray | Clinical approach to inborn errors of metabolism in paediatrics[END_REF]. The OA and cortical blindness that occur early in the course of Krabbe diseasegloboid cell leukodystrophy, galactosylceramid lipidosisare a direct consequence of the severe loss of myelin and oligodendroglia that is characteristic of this disorder. Although the OA develops early in the disease course, it is usually overshadowed by the neurological deterioration. OA is also frequent in metachromatic leukodystrophy and may result in severely impaired vision.

OA is a frequent early presenting sign of primary -Leber hereditary optic neuropathy, respiratory chain deficiencies, pyruvate dehydrogenase deficiency, biotinidase deficiency, Costeff optic atrophy syndromeor secondaryorganic aciduriasmitochondrial dysfunction. By contrast, OA appears to be a rather rare ocular finding in disorders of complex lipids synthesis compared to retinal dystrophies. Nonetheless, visual loss and OA are early presenting sign in several disorders of dolichol synthesis and remodeling pathway (Lefeber this issue). It is also a very frequent and early significant sign in some NBIA -INAD and MPAN -,in which an impairment of mitochondrial function is strongly suspected in disease development and/or progression. In this respect, it is relevant that the mitochondriaassociated membrane of the endoplasmic reticulum is major site of phospholipid biosynthesis and trafficking (Tiranti this issue).

Glaucoma is characterized by the progressive loss of visual fields due to the degeneration of the optic nerve, usually associated with increased intraocular pressure. Early onset glaucoma is a major diagnostic sign in Charcot Marie Tooth disease type 4B2, due to mutations in the gene SBF2 that is involved in phosphoinositide metabolism. [START_REF] Ferguson | Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome)[END_REF], which highlights the potential role of complex lipids in inflammation [START_REF] Csaki | Lipins, lipinopathies, and the modulation of cellular lipid storage and signalling[END_REF].

Dermatological presentations -

Orthopedic presentations -Table 6

Over 20 inborn errors affecting the synthesis or remodeling of phosphatidylcholine, phosphatidylserine, phosphatidylinositol, plasmalogens or cholesterol present with major bone and cartilage involvement. Schematically, 3 clinical entities may be recognized: congenital bone dysplasia, overgrowth disorders and inflammatory presentations.

Congenital bone dysplasia

Beside rhizomelic chondrodysplasia punctate (Brites this issue) and the already wellknown defects of cholesterol and plasmalogen biosynthesis responsible for a variety of bone dysplasia and polymalformative syndromes (Waterham 2012), several original entities affecting phospholipids metabolism have been recently described.

They involve mostly the synthesis, transport or activating pathways of phosphoserine (Wortmann this issue) and phosphatidyl inositides [START_REF] Balla | Phosphoinositides : Tiny lipids with giant impact on cell regulation[END_REF]): (i)

Lenz-Majewski syndrome, a sclerosing bone dysplasia is caused by a gain of function mutation in the gene encoding phosphatidylserine synthase 1 (PTDSS1), which impairs the negative feedback regulation of the enzyme by its reaction product phosphoserine (Sousa et al, 2014, Wortmann this for the regulation of phosphatidylinositol 3,5-phosphate (PI(3,5)P2) [START_REF] Campeau | Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase[END_REF]; and (iv) opsismodysplasia, a severe chondrodysplasia is due to a deficiency in inositol-1,4,5-triphosphate 5-phosphatase INPPL1 [START_REF] Huber | Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia[END_REF].

Segmental overgrowth disorders with congenital lipomatosis

The molecular etiology of somatic overgrowth syndromes has been recently clarified

Inflammatory presentations

Recurrent aseptic necrosis and medullary infarction of long bones in an inflammatory context are a frequent diagnostic finding in Majeed syndrome and Gaucher disease.

These symptoms represent a major clinical concern.

Hepatic presentations -Table 7

Complex lipids synthesis and remodeling disorders may be associated with 3 preponderant hepatic presentations.

The first presentation is a transient neonatal to early infantile cholestatic jaundice and/or liver failure followed by a neurodegenerative disorder. Beside the well-known Niemann-Pick type C disease (Vanier 2010), cholestatic jaundice may be the first manifestation of several diseases affecting the synthesis of cholesterol and bile acids. In most cases, the jaundice spontaneously resolves but psychomotor delay, peripheral neuropathy and/or motor dysfunction develop during the first decade or even later. In the so-called infantile Refsum diseasea peroxisome biogenesis defectthe neonatal jaundice is commonly followed by a 1 to 3 years phase of Major hepatosplenomegaly is another preponderant diagnostic sign, evocative of many lysosomal disorders involving the catabolism and recycling of complex sphingolipids. Mevalonate kinase deficiency presents early in life with acute recurrent inflammatory crisis, fever, skin rashes, arthralgia, hepatosplenomegaly and severe recurrent anemia [START_REF] Houten | Isoprenoid biosynthesis in hereditary periodic fever syndrome and inflammation[END_REF]. Disorders of complex lipids biosynthesis may also involve the immune system : (i)

PIK3CD mutations cause a combined immune deficiency; (ii),PIK3R1 mutations are responsible for an autosomal recessive agammaglobulinemia; and (iii) the recently described deletions of PLCG2, which encodes phospholipase Cγ(2)an enzyme expressed in B cells, natural killer cells and mast cells -, present with cold urticaria, immunodeficiency and autoimmunity [START_REF] Ombrello | Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions[END_REF].

Conclusion

This review attempts to give a clinical overview of disorders affecting the synthesis and remodeling of phospholipids and other complex lipids. Many metabolic and genetic factors may account for the clinical diversity of these disorders. The quantitative importance of lipids in the nervous system makes the brain and peripheral nerves a privileged target for these lipids synthetic defects. Mitochondrial membranes that are very rich in cardiolipin and phosphoethanolamine should be particularly vulnerable to mutations affecting these molecules. The tissue specificity of some complex lipid molecules also probably accounts for some specific clinical presentations. Hence the high concentration of cardiolipin in muscle and its very small content in the brain may underlie the predominant muscle/cardiac presentation of Barth syndrome with no or minimal involvement of the nervous system. Similarly, the confinement to skeletal muscles of clinical manifestations of Lipin-1 mutations might be related to the nearly ubiquitous expression of the 2 other LPIN genes (LPIN2 and LPIN3). The constant CNS involvement observed in phospholipase A2

deficiency is probably related to the major and predominant expression of this enzyme in the brain even if the clinical heterogeneity is still poorly understood.

HSP with ichthyosis:

-Sjögren-Larsson syndrome: mild to moderate DD, retinopathy, pseudobulbar dysarthria. Brain MRI: Delayed myelination and abnormal lipid peak on MRS (white matter)

-HSP with ichthyosis resembling Sjögren-Larsson syndrome.

Severe DD, refractory seizures and cataracts.

HSP with variable degrees of cognitive involvement and brain MRI findings:

-SPG56: "Pure" HSP or associated with variable degree of DD and infraclinic axonal neuropathy. Brain MRI: normal or thin CC with basal ganglia calcifications.

- -ALOX3 /ALOX 12B defects present with non bullous congenital ichthyosiform erythrodermia (NCIE). Patients are born as collodion baby.

-CYP4F2 Most of the patients are not born as collodion babies but present a more erythrodermal status of the skin at birth. After birth, they present with generalized LI mostly on the periumbilical region, the lower part of the body and on the buttocks. Hyperlinearity of palms and soles similar to that found in ichthyosis vulgaris is constant. There are scales on the scalps in all patients.

-Phospholipase A1 deficiency born as collodion babies, later having generalized ichthyosis with fine white scales and moderate erythroderma and palmoplantar keratoderma. No lipid vacuoles.

ABCA12 lipid transporter

Lipoxygenase

-3 12(R)-Lipoxygenase CYP4F2 (leukotriene B4-v- hydroxylase) Phospholipase A1 ABCA12 (AR) ALOXE3 (AR) ALOX12 (AR) FLJ39501 (AR) PNPLA1 (AR)

ICHTHYOSIS SYNDROMIC

Congenital to early infantile <4months

Syndromic congenital ichthyosis

-Acute neuronopathic Gaucher disease perinatal form: Transient collodion baby with severe multivisceral failure, hydrops foetalis, hepatosplenomegaly, pancytopenia, arthrogryposis (40%), brainstem dysfunction, pyramidal signs, opisthotonos.

-Ceramide synthetase 3 deficiency: One of the affected girls presented at birth an extreme ectropion at eclabium with collodion membrane followed by a moderate lamellar ichthyosis, scaling of the scalp and a pronounced keratotic lichenification with prematurely aged appearance. Four additional Tunisian patients were affected with a contiguous gene deletion syndrome involving exon 13 of CERS3 and ADAMTS17. These patients presented a combination of the above ichthyosiform phenotype and the symptoms of Weill-Marchesini-like syndrome due to ADAMTS17 mutations.

Ichthyosis with spastic paraplegia (SP)

-Sjögren-Larsson syndrome : ichthyosis with severe pruritis, early hypotonia, generalized scaling sparing the face, yellow lichenification of neck, flexures, and abdomen, hypohidrosis, HSP over the first 2y, cataracts, macular dystrophy, mild DD. Brain MRI: delayed myelination and abnormal lipid peak. Pruritis improved by Zileuton.

-Neuro-ichythyotic syndrome resembling severe Sjögren-Larsson syndrome: collodion babies, later having generalized ichthyosis with predilection to the neck and diaper areas then to the hands and feet, severe DD, Acid B Glucosidase (Glucocerebrosidase)

Ceramide synthase 3

Fatty acid aldehyde dehydrogenase

Fatty acid elongase

GBA (AR) CERS3 (AR) ALDH3A2 (AR) ELOVL4 (AR)

Syndromic ichthyosis with chondrodysplasia punctata

-X-linked syndromic ichthyosis: severe generalized nonpruritic ichthyosis ,palms and soles spared (most cases) pigmented desquamation, corneal opacities, DD, small stature, hypogonadism, chondrodysplasia punctata.

-X-linked dominant chondrodysplasia punctata Diffuse cutaneous lesions (may be transient), chondrodysplasia punctate, rhizomelic asymmetric dwarfism, cataracts, DD, only in girls (Conradi-Hunermann syndrome). Resemble Child syndrome and RCDP.

-RCDP type II and III :Ichythyosis with severe proximal shortening of limbs,typical facies dysmorphism,cataracts, calcific stippling of epiphyses,coronal cleftsof vertebral bodies,multiple join contractures,severe growth and DD.

Ichthyosis and dry skin with multiple congenital anomalies

VARIABILIS (EKV)

4 th to 5 th decades (neurologic signs) infancy .First, erythematous and hyperkeratotic plaques over the dorsal aspects of the hands and feet, the elbows, the ankles, and the external ears. The hyperkeratosis usually is more prominent than the erythema. Second, transient, figurate, and erythematous patches are observed over the legs, thighs, and buttocks. Both types of lesions are symmetrically distributed and vary in severity. The lesions disappear after the patient is 25 years of age. The onset of gait ataxia usually occurred in the fourth or fifth decade of life. The progression of gait disturbance is very slow.

CONGENITAL GENERALIZED LIPODYSTROPHY

Yunis-Varon syndrome (AR)

Wide fontanels with calvarial dysostosis, aplasia or hypoplasia of the clavicles and phalanges in the hands and feet, absence of thumbs and halluces. Pelvic bone dysplasia, absent sternal ossification centers and fractures are also frequent. Common features include diffuse brain atrophy, sparse and pale hair, facial dysmorphism.

Phosphoinositide phosphatase (FIG4)

(required for the regulation of PI(3,5)P2 levels)

PIK3R2

Campeau 2013

PZO Biogenesis defects (AR)

Classical Zellweger syndrome may present with chondrodysplasia punctata less widespread than in RCDP.

Several peroxins

PEX genes

Poll The 2012

Refsum disease (AR)

Skeletal malformations in 50% of patients: symmetric epiphyseal dysplasia in the knee, joints, elbows and shoulders; bilateral shortening or elongation of the 3 rd and 4 th metatarsal bones, syndactyly and shortened digits.

Phytanic acid hydroxylase

PHYH

Child syndrome (X-linked dominant))

CHILD syndrome (congenital hemidysplasia with ichtyosiform erythroderma and limb defects) presents with skin and skeletal abnormalities similar to those observed in CDPX2 patients but with a striking unilateral distribution affecting the right side of the body more often than the left. Alopecia, nail involvement and limb reduction defects with calcific stippling of the epiphysis are common on the affected side. There is no cataract.

3-hydroxysterol dehydrogenase

NSDHL

Waterham 2006

Smith Lemli Opitz (SLOS syndrome) (AR) Cataract may also be present as early as 5 years of age. Some patients present with persistent diarrhea from early childhood.

Motor dysfunction (spastic paresis, cerebellar ataxia) frequently develops in the second or third decade of life. Xanthomata are observed within the second decade.

á-Methylacyl-CoA Racemase Deficiency (AMACR) Neonatal cholestatic liver disease was documented in an infant with AMACR deficiency who presented with a coagulopathy due to vitamin K deficiency; a sibling had died of a major bleed with the same cause.

The infant had mild cholestatic jaundice with raised aspartate aminotransferase and, in contrast to 3â-dehydrogenase deficiency, 5â-reductase deficiency and CTX, elevated ã-GT.

Oxysterol 7á-Hydroxylase Deficiency Oxysterol 7á-hydroxylase may present in the first 3 months of life with severe cholestasis, cirrhosis and liver synthetic failure. One infant presented with liver failure and hypoglycaemia at 3 months but recovered completely with chenodeoxycholic acid treatment. Oxysterol 7á-hydroxylase deficiency has also been identified as a cause of a recessive form of hereditary spastic paraplegia (SPG type 5).

Hepatosplenomegaly

With storage signs (lysosomal disorders)

Neonatal to late infancy

First weeks of life

Gaucher disease. The perinatal lethal form is associated with hepatosplenomegaly, pancytopenia and skin changes with hydrops fetalis in many cases. Children often show severe splenomegaly, generally associated with hepatomegaly, . This may lead to anemia, thrombocytopenia and bleeding tendency. Children may show delayed growth and menarche. Subcapsular splenic infarctions may cause attacks of acute abdominal pain and medullary infarction of long bones, excruciating pain often referred to as bone crises.

Niemann Pick disease type C. Isolated hepatosplenomegaly or splenomegaly can start at this age. In the severe early infantile neurological onset form, infants with a pre-existing hepato splenomegaly (often with a history of neonatal icterus) show an early delay in motor milestones that becomes evident between the age of 9 months and 2 years, and hypotonia. Most never learn to walk. A loss of acquired motor skills is followed by spasticity with pyramidal tract involvement and mental regression.

Wolman disease presents in the 1 st week of life with poor feeding, vomiting, diarrhea, severe failure to thrive, abdominal distension, hepatosplenomegaly with mesenteric adenopathy and bilateral adrenal calcifications at abdominal ultrasound. The psychomotor development is normal.

Classic Niemann-Pick

With inflammatory crisis and anemia

Neonatal to first days

Late infancy to adulthood

First year of 5-10 months, when the child shows hypotonia, progressive loss of acquired motor skills, lack of interest in the surroundings and reduction of spontaneous movements.

GM1 gangliosidosis (Landing disease) The typical early infantile form (or type 1) presents with hypotonia in the first days or weeks of life, with poor head control. The arrest in neurological development is observed at 3-6 months of age. Feeding difficulties and failure to thrive are common. Many infants have facial and peripheral edema. In typical cases, dysmorphic features resembling Hurler syndrome may be present. Hepatomegaly and later splenomegaly are almost always present. Dorsolumbar kyphoscoliosis is common.

Prosaposin deficiency presents as a severe neurovisceral storage disease manifesting immediately after birth with rapidly fatal course and death between 4 and 17 weeks of age. The patients have hepatosplenomegaly, hypotonia, massive myoclonic bursts, abnormal ocular movements, dystonia and seizures.

Niemann Pick disease type B chronic, non-neuronopathic disease presents typically with splenomegaly or hepatosplenomegaly in late infancy or childhood but discovery may occur at any point from birth until late adulthood. Bruising and epistaxis are frequent. Hypersplenism may occur. The most constant associated signs are radiographic abnormalities of the lung (diffuse, reticulonodular infiltrations) and interstitial lung disease with variable impairment of pulmonary function.

Mevalonate kinase deficiency present with characteristic episodes of high fever and inflammation with abdominal pain, vomiting, diarrhea, lymphadenopathy, hepatosplenomegaly, skin rash and recurrent non regenerative anemia.

  photoreceptor outer segment membrane is essential to the photon capturing and signaling functions of rhodopsin. The rearrangement of phospholipids in the bilayer accompanies the formation of the active intermediates of rhodopsin following photon absorption. ABCA4 is implicated in the transport of a retinal phospholipid compound across membranes of the photoreceptor outer segment disc. All-trans retinal released from rhodopsin is reduced to all-trans retinol and subsequently shuttled to the RPE cells where it is sequentially converted back to 11-cis retinal for the regeneration of rhodopsin[START_REF] Molday | Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration[END_REF]. These last steps involve consecutively lecithin:retinol acyl transferase (LRAT) and RPE 65 isomerase. All these steps have been found implicated in various forms of RP and Leber congenital amaurosis (LCA)[START_REF] Mackay | Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations[END_REF].

  and allowed the clinical delineation and natural history of the PIK3CA-related overgrowth spectrum[START_REF] Keppler-Noreuil | Clinical Delineation and Natural History of the PIK3CA-Related Overgrowth Spectrum[END_REF][START_REF] Lindhurst | Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA[END_REF]. The spectrum of diseases associated with PIK3CA mutations include fibroadipose overgrowth, hemihyperplasia multiple lipomatosis, congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal syndrome (CLOVES), macrodactyly, and the megalencephaly-capillary malformation syndrome (MCAP). It appears that all these phenotypes have a considerable overlap and are associated with somatic gain of functions of phosphoinositol kinase 3 resulting in an over-activation of the phosphatidylinositol/AKT/mTOR pathway. PIK3CA mutations are detected in affected tissues or cultured cells at varying levels, but not in the blood or saliva. There is not a clear correlation between the mutation level in either tissues or cultured cells to either the type or the severity of the manifestations. Apart from the class IA of PI3Ks, human diseases are rarely caused by activating mutations of inositide lipid kinases. Moreover, loss of function of inositol lipid kinases is rarely seen in human diseases. The only report on an inactivating mutation of the PIP 5kinase I gene was associated with severe developmental abnormalities with perinatal lethality[START_REF] Narkis | Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI gamma of the phosphatidylinositol pathway[END_REF]. Conversely, an increasing number of rare human diseases such as Joubert syndrome, Lowe syndrome, Charcot-Marie-Tooth disease type 4B1 or X-linked myotubular myopathy are linked to phosphoinositide phosphatase defects and cause very specific phenotypes[START_REF] Balla | Phosphoinositides : Tiny lipids with giant impact on cell regulation[END_REF].

  failure to thrive with hepatomegaly, osteoporosis and hypocholesterolemia before neurologic symptoms, RP and deafness arise (Poll-The 2007). Megdel syndrome also presents first with recurrent episodes of liver failure, similar to what is seen in mitochondrial DNA depletion syndromes, before the onset of dystonia and a Leighlike encephalopathy (Sarig et al 2013; Wortmann this issue).

Finally

  , non-alcoholic liver steatosis is a presenting sign in several IEM involving triglyceride biosynthesis. Indeed, the liver is a central organ in the regulation of triglycerides metabolism; it participates in triglyceride synthesis, export, uptake and oxidation. Hepatocytes can shift from intensive fatty acid synthesisin fed stateto rapid fatty acid breakdownduring starvation. Massive fatty liver, partly reversible, is an almost constant finding in many mitochondrial fatty acid oxidation disorders during acute crises[START_REF] Saudubray | Recognition and management of fatty acid oxidation defects : a series of 107 patients[END_REF]. Chronic hepatosteatosis, considered as the fundamental cause of hepatic injuries, inflammation and fibrosis are often found in individuals with defect in triacylglycerol metabolism. Patients may present (i) either with a preponderant hepatomegaly with hypertriglyceridemia, as observed in individuals with Chanarin-Dorfman syndrometriglyceride lipase or glycerol-3phosphate dehydrogenase deficiency (Aguilera-Méndez et al, 2013; Wu and Mitchell this issue); or (ii) as a lipodystrophy with insulin resistance and diabetes, like in the Berardinelli-Seip syndrome (Wu and Mitchell this issue) and the most recently described late onset form of choline-phosphate cytidylyltransferase A deficiency (Payne et al 2014). 7. Other presentations Several renal presentations have been described so far: (i) Mutations in DGKE result in diacylglycerol kinase epsilon deficiency and cause renal microangiopathies, leading either to a membranoproliferative glomerulonephritis or an early onset atypical haemolytic-uremic syndrome (Lemaire et al 2013; Ozaltin et al 2013; Westland et al. 2014; Wortrmann this issue); (ii) Nephrotic syndrome is a major manifestation of coenzyme Q synthesis defects (Salviati this issue) and a preponderant presenting sign in PLCE1 mutations responsible for the nephrotic syndrome type 3; (iii) Renal Fanconi syndrome with mental retardation and cataract are cardinal signs of Lowe syndrome due to OCRL1 mutations (Attree et al 1992; Suchy et al 2002) -OCRL mutations are also found in some forms of Dent disease without any cataract (Hoopes 2005); (iv) Nephronophthisis may be one of the symptoms observed in Joubert syndrome due to INPP5E mutations, now included in the new emerging group of ciliopathies (Bielas et al 2009); and (v) Renal cysts are a cardinal sign in the hepato-cerebro-renal Zellweger syndrome resulting from peroxisome biogenesis defects.

  LCHAD deficiency. A few patients with LCHAD deficiency present in the first 3 months of life with transient cholestatic jaundice followed by the classic manifestation of LCHAD disease (recurrent attacks of hypoglycemia and myoglobinuria, cardiac features, peripheral neuropathy and retinitis pigmentosa)

  Disease Type A. Presents with vomiting and diarrhea, failure to thrive, prominent and progressive hepatosplenomegaly and lymphadenopathy, in most cases before 3-4 months of age and sometimes earlier. Hypotrophy is a frequent finding. Neurological examination is essentially normal until the age

Table 4 Cataract

 4 Lens membrane contains the highest cholesterol content of any known membrane, indicating the importance of normal cholesterol metabolism in lens maintenance. At least 3 inborn errors of cholesterol biosynthesismevalonate kinase deficiency,

Conradi Hunermann syndrome, Smith Lemli Opitz syndromeand one disease of bile acids synthesiscerebrotendinous xanthomatosismay be associated with opacities of the crystalline lens. Syndromic cataracts may also be observed in several other IEM related to complex lipids synthesis, either as a diagnostic sign or as an isolated presenting sign like in Lowe syndrome.

  acuity in their first or second decade of life. Progressive decrease in visual acuity generally occurs throughout life with values reaching 20/200 or worse in the final stages of the disease. Stargardt patients also show a delay in dark adaptation and variable loss in color vision. Ophthalmoscopic examination of

	Stargardt patients typically reveals bilateral atrophic changes in the macula
	associated with the degeneration of photoreceptor cells and the underlying RPE. Two
	genes associated with inherited macular degenerative diseases encode proteins
	whose function is to process lipids in photoreceptor cells: ABCA4 mutations cause
	the autosomal recessive Stargardt macular degeneration and ELOVL4 mutations
	lead to the autosomal dominant Stargardt-like disease (Molday 2010). In addition to
	Stargardt disease, mutations in ABCA4 are known to result in 2 more severe, but
	clinically distinct, retinal degenerative diseases: a cone-rod dystrophy and the
	autosomal recessive retinitis pigmentosa 19. Cone-rod dystrophy (CRD) is a retinal
	disorder in which cone photoreceptor cells degenerate before rod cells. Mutations in
	ABCA4 account for 30%-60% of autosomal recessive CRD. In some cases, Stargardt
	disease can evolve into a CRD. Likewise, it is now generally believed that mutations
	in ABCA4 result in a spectrum of related retinal dystrophies, the severity of which
	depends on the type of mutations, its effect on protein function, age of onset and
	genetic modifiers
	macular atrophy, peripheral white dots at the level of the RPE and retinal
	pigmentation. The full-field electroretinogram (ERG) is usually non-detectable with
	conventional ERG testing or severely decreased before the age of 1 year. LCA,
	EORD and RP may be considered as a continuum spectrum of retinal dystrophies, in
	which LCA represents the most severe form due to its age of onset and functional
	outcome.

The term juvenile RP has also been used to describe EORD. Autosomal recessive RP falls into this spectrum of disorders with onset typically later in childhood or beyond. Depending on the age at diagnosis, the retinal appearance may be normal or there may be a variety of abnormalities including vascular narrowing, Stargardt disease is the most common autosomal recessive, early onset macular dystrophy. Affected individuals display significant loss in central vision with a marked reduction in visual

Table 5

 5

	About 30 inherited disorders of complex lipids synthesis, remodeling ,catabolism and
	transport presenting with ichthyosis have been described so far. According to the
	most recent ichthyosis consensus conference (Oji et al 2010), inherited ichthyoses
	belong to a large and heterogeneous group of mendelian disorders of cornification
	and involve the entire integument. This classification remains clinically based and
	distinguishes between syndromic and non syndromic ichthyosis forms. Bullous
	ichthyosis/epidermolytic hyperkeratosis was redefined as keratinopathic ichthyosis.
	Autosomal recessive congenital ichthyosis (ARCI) refers to harlequin ichthyosis,
	lamellar ichthyosis, and congenital ichthyosiform erythroderma. At least 6 inherited
	lipids synthesis disorders are responsible for non syndromic ARCI, all but one -
	linked to epidermal lipase N deficiency -presenting at birth with a collodion baby
	aspect. The vast majority of ichthyosis linked to complex lipids disorders present as
	neuro-cutaneous syndromes, chondrodysplasia punctata or multiple congenital
	anomalies -CDG syndromes, neuro laxova syndrome. Among the neuro-cutaneous
	syndromes comprising spastic paraparesis, Sjögren-Larsson syndrome -ALDH
	deficiency -presents at birth with a very severe pruriginous ichthyosis that responds
	dramatically to Zileuton (Willemsen et al 2001). Sterol methyl-C4 oxidase, a sterol
	metabolism disorder, is another treatable ichthyosis with a spectacular improvement
	on statin and cholesterol supplement (He et al 2011).

  distinct entities, but rather clusters on a continuous spectrum like for the PNPLA6-associated diseases, ranging from Boucher-Neuhauser syndrome, Gordon Holmes syndrome, spastic ataxia and pure HSP. Similarly, LCA, EORD and RP may be considered as a continuum spectrum of retinal dystrophies. Likewise,

	PREDOMINANT	AGE AT		MAJOR SYMPTOMS and BRAIN IMAGE		DEFECTIVE	DEFECTIVE	BIBLIOGRAPHIC
	NEUROLOGICAL	ONSET							ENZYME	GENE	REFERENCES
	SYNDROME								(Inheritance)
	HEREDITARY	Infantile <2	HSP related to "INAD" phenotype: truncal hypotonia,
	mutations in ABCA4 result in a spectrum of related retinal dystrophies including some years psychomotor deterioration, cerebellar ataxia, early onset optic SPASTIC PARAPARESIS atrophy, abnormal EEG pattern (fast rhythms). Brain MRI: (SP) cerebellar atrophy, high intensity cerebellar cortex;
	forms of Stargardt disease.	hypointensities pallidum and SN.
	Awaiting for a more comprehensive overview of this very complex part of cellular
	metabolism, a clinical approach based on the preponderant presenting symptoms
	remains therefore the only available one at bedside. The careful grouping of patients
	in well-defined clinical entities may provide algorithms for orientating metabolic (e.g.,
	choline-phosphate	cytidylyltransferase	A,	which	may	present	as	a
	spondylometaphyseal dysplasia with cone rod dysfunction or as a congenital
	lipodystrophy with fatty liver disease but any bone or retina involvement (Payne et al
	2014). Tissue specificity might also be responsible for many non syndromic
	phenotypes, like (i) immune deficiencies syndromes related to mutations in genes
	specifically expressed in lymphocytes; (ii) congenital ichthyosis related to mutations
	in genes specifically expressed in keratinocytes such as LIPN encoding epidermal

It is noteworthy that identical mutations affecting the same enzyme can give rise to very different phenotypes like in ELOVL4 mutations which may present as an autosomal dominant spinocerebellar ataxia with erythrokeratodermia (Cadieux-Dion 2014), a dominant form of Stargardt disease type 3 or a recessive neuro-ichthyotic syndrome resembling a severe presentation of Sjögren-Larsson disease. Another example of such an intriguing phenotypic heterogeneity are mutations in PCYT1A, encoding lipase N

[START_REF] Israeli | A Mutation in LIPN, Encoding Epidermal Lipase N, Causes a Late-Onset Form of Autosomal-Recessive Congenital Ichthyosis[END_REF]

) and PNPLA1 encoding a PNPLA protein involved in glycerophospholipid synthesis

[START_REF] Grall | PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans[END_REF]

); (iii) retinal dystrophies; or (iv) renal presentations. It must be stressed that many apparently well clinically defined syndromes are not lipidomic approaches) and genetic (e.g., exome sequencing) investigations. Of note, these complex molecules synthesis defects are at the crossroad of classical IEM due to an enzymatic block on a catabolic pathway and IEM affecting the synthesis and stability of structural molecules. The concept of complex molecules synthesis defects also opens the window to promising therapeutic trials for example by providing the distal missing compound as it has been successfully done in cerebrotendinous xanthomatosis

[START_REF] Berginer | Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid[END_REF]

, coenzyme Q synthesis defects (Salviati this issue), serine synthesis defects

[START_REF] Méneret | A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy[END_REF]

and serine metabolism defects involved in de novo biosynthesis of glycosphingolipids

[START_REF] Garofalo | Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1[END_REF]

.

Table

  Click here to download Table: Table 1 Rev CNS final .docx

			patient developed West syndrome.			2012
		Childhood to	HSP with variable degrees of cognitive involvement and brain Choreoathetosis associated with early onset epilepsy, DD,	Lactosylceramide	ST3GAL5 (AR)	Simpson et al,
		adulthood	HSP with severe sensorymotor polyneuropathy, abnormal MRI findings: Childhood onset HSP and DD and later dystonia, dysarthria and optic atrophy and hyperpigmented lesions. Early refractory seizures may appear also in PLA2G6, FA2H and	Arylsulfatase family CoA synthase α-2,3 sialyl	ARSI (AR) COASY (AR)	Novarino et al, Dusi et al, 2014 2004; Fragaki et
			gait, pes equinovarus and borderline intelligence. Brain MRI: spastic-dystonic tetraparesis Brain MRI: T2 hyperintensity and ELOVL4 mutations	member I deficiency transferase (GM3		2014 al, 2013
			thin CC and cerebellar hypoplasia ( 1 single case described) -HSP with border line intelligence and abnormal hand swelling of both caudate nuclei and putamen, mild Mental Retardation/DD and multiple abnormalities:	GPI-Anchor synthase)	PGAP1 (AR)	Novarino et al,
		Adolescence	movements. Brain MRI: prominent cortical sulci and widened hyperintensity of both thalami. T2 hypointensity of the	synthesis pathway		2014
		to adulthood	sylvian fissures (1 case described) pallidum may appear later. -Coloboma, ear abnormalities, congenital heart disease and		PIGL	Ng et al, 2012
			Dystonia-Parkinsonism (PARK14). Dyskinesia associated with icthyosiform dermatosis, also known as Zurich	Calcium	PLA2G6 (AR)	Kurian and
	ATAXIA	Infantile to adolescence	+/-"Pure" HSP, SPG28; slowly progressive (variable association -SPG26: HSP that may associate cognitive impairment, ARCA with hypogonadotropic hypogonadism: -Boucher-Neuhäuser syndrome (MIM 215470), with tremor including a pill-rolling rest component, rigidity and severe bradykinesia with a good response to L-Dopa; Levy body neuroectodermal syndrome	Phospholipase A1 GM2 synthase Neuropathy target enterase (NTE) independent phospholipase A2γ	DDHD1 (AR) B46ALNT1 PNPLA6 (AR)	Bouslam et al, Boukhris et al, Synofzik et al, 2014 Hayflick, 2013
			with axonal neuropathy, distal sensory loss, and cerebellar eye cerebellar ataxia, dystonia, muscle wasting, axonal neuropathy chorioretinal dystrophy. pathology. Psychiatric symptoms may precede motor signs.	deficiency	(AR)	2005 2013; Harlalka et
			movement disturbance) and psychiatric signs. Normal brain MRI. -Gordon Holmes syndrome (MIM 215470), with brisk reflexes. Sensory motor axonal neuropathy may be present but not Brain MRI: may be normal or show cortical atrophy +/-white matter changes. -Severe DD, hypotonia, seizures and multiple congenital		PIGN, PIGA	al, 2013 Krawitz et al,
	NBIA	Childhood to adolescence	HSP and cerebellar dysfunction: constant. Brain MRI: cerebellar atrophy. Pons and pituitary may be atrophic. Dystonia-Parkinsonism may be present in any cause of NBIA abnormalities (MCAHS 1 due to PIGN and MCHAS due to PIGA)	Calcium independent	PLA2G6 (AR) (PLAN, NBIA2)	Kurian and Hayflick 2013; 2013
	EPILEPSY	and adulthood Childhood to adulthood Infantile	-SPG35: HSP that may associate cognitive decline, epilepsy, mild to severe dystonia, mild to severe optic atrophy. Brain MRI: bilateral T2 pallidum hypointensities, PVWMH, thin CC, pontocerebellar atrophy ARCA +/-other manifestations such as migraines, seizures, psychiatric symptoms syndrome. Early severe epileptic encephalopathy, pharmacoresistant, with choreoathetosis, DD, optic atrophy and hyperpigmented Dystonia may be present in complex forms of HSP, especially SPG26 (B4GALNT1), SPG35 (FA2H) and SPG56 (CYP2U1). lesions.	Fatty acid-2 hydroxylase phospholipase A2γ Coenzyme Q10 deficiency Lactosylceramide α-2,3 sialyl synthase) transferase (GM3	FA2H (AR) COQ8-ADCK3 (AR) ST3GAL5 (AR)	Dick et al, 2010; Kruer et al, 2010 Schneider et al, 2013 Simpson et al, Lagier-Tourenne 2008; Blumkin et al 2014 2004; Boccuto et al, 2014
	COMPLEX OR MOVEMENT DISORDERS SYNDROMIC DEVELOPMENTAL DELAY/ INTELECTUAL DISABILITY	Infantile	-HSP that may associate ataxia and hypogonadism -SPG46: HSP that may associate variable degree of DD, axonal neuropathy, cataract, hearing loss. Brain MRI may show thin CC and cerebellar atrophy. HSP and distal muscle wasting with spinal cord atrophy, SPG39. Progressive disease Childhood onset gait impairment, spastic quadriparesis, severe ataxia and dystonia. Seizures and divergent strabismus may also be present. Similar to INAD. Brain MRI: T2 hypointensity of the pallidum, prominent pontocerebellar atrophy, mild cortical atrophy, white matter abnormalities and CC thinning. Ataxia and gait impairment may be present as an associated Parkinsonism may appear very often at late stages of sign in diverse disorders that cause HSP or NBIA as neurodegenerative diseases regardless of the molecular origin predominant phenotypes. Leigh-like syndrome due to MEGDEL (3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like) syndrome. Neonatal hypoglycemia followed by transient hepatic failure. By age 2 years progressive deafness, dystonia, spasticity and psychomotor stagnation. Brain MRI: Leigh-like Leigh syndrome with multisystem involvement (nephropathy and cardiomyopathy) involvement of expressive language. Coarse facial features. Epilepsy may be present. Anorectal abnormalities and other malformations may be present. In PIGW (1 case described) the epilepsy and intellectual disability. Diverse GPI-anchor deficiencies may be associated with bilateral basal ganglia involvement Venous thrombosis and absence seizures (PIGM) Syndrome. Global developmental delay with marked HPMRS: Hyperphosphatasia and Mental Retardation MCAHS1 and 2.	Neuropathy target esterase (NTE) Non-lysosomal b-glucosidase 2 Neuropathy target enterase (NTE) Pantothenate kinase 2 Fatty acid-2 hydroxylase Coenzyme Q deficiency biosynthesis pathway Protein localized at (MAM) mitochondrial associated proteins Defects in the GPI-anchor-anchor-Defects in the GPI-pathway biosynthesis	PNPLA6 (AR) GBA2 (AR) PNPLA6 (AR) PANK2 (AR) FA2H (AR) COQ1-PDSS2 (AR) PIGO , PIGW SERAC1 (AR) PIGM, PIGN, PIGA PGAP3, PIGV PGAP2,	Synofzik et al, 2014 Martin et al, 2013; Hammer at al, 2013 Rainier et al, 2008 Kurian and Hayflick 2013; Schneider et al, 2013 Kruer et al, 2010 Rotig et al, 2000 2013 Chiyonobou et al, Wortmann et al, 2012 Almeida et al, 2006, Krawitz et 2012, 2013 Krawitz et al, al, 2013

Static encephalopathy in childhood with milder signs than in the INAD phenotype and late onset neurodegeneration in adolescence. Brain MRI: T2 hypointensity of the pallidum and cerebellar atrophy are not an universal feature. MRI may be normal or show cortical atrophy +/-white matter changes Classical PKAN (mean age: 3.4 years). Dystonia (mainly face and limbs) is always present. Pigmentary retinopathy. Atypical PKAN (mean age: 14 years). Gait abnormality, dystonia, dysarthria, neuropsychiatric manifestations and cognitive decline. Pyramidal signs. Brain MRI: T2 hypointensity of the pallidum centered by T2 hyperintensity: "Eye-of-the-tiger" sign (may appear later) Infantile DD and/or ID may be present as an associated sign in diverse disorders that cause HSP, NBIA or movement disorders as predominant phenotypes.

Table 1 Neurological presentations: central nervous system involvement Abbreviations:

 1

	PERIPHERAL	AGE AT	MAJOR SYMPTOMS	DEFECTIVE	DEFECTIVE	BIBLIOGRAPHIC
	NEUROPATHY and	ONSET		ENZYME	GENE	REFERENCES
	SPINAL CORD involvement				(Inheritance)
	SENSORY, AUTONOMIC		Progressive loss of pain and temperature sensation spreading
	NEUROPATHY		from the distal limbs.
		Adolescence	HSAN type 1 is the most common form.
		to adulthood
			Most cases: autosomal dominant, late onset (typically
			between the 2nd and 4th decade), slow progression, distal
			sensory involvement (plantar ulcers predominantly affecting
			the lower limbs and lancinating pain attacks). Muscle
			weakness and cataract. Motor neuron degeneration can
			occur. Considerable clinical heterogeneity in the time of
			onset and the severity of the symptoms. SPTLC1 and SPTCL2
			are the most common mutations.
		Early
		childhood

AR: autosomal recessive; ARCA: autosomal recessive cerebellar ataxia. CC: corpus callosum. DD: Developmental delay; ELOVL4: elongase/elongation of very long chain fatty acids deficiency; FA2H: Fatty acid 2-hydroxylase deficiency. FALDH: Fatty aldehyde dehydrogenase deficiency; GM3S: gangliosidosis type 3 synthase deficiency; GP: globus pallidum; GPI: glycosylphosphatidylinositol. HPMRS: Hyperphosphatasia and Mental Retardation Syndrome. HSP: hereditary spastic paraparesis; ID: Intellectual disability; iPLA1: intracellular phospholipase A1. INAD: infantile neuroaxonal dystrophy; LeukoD: leukodystrophy; MCAHS: multiple congenital abnormalities, hypotonia and seizures. NBIA: neurodegeneration associated with brain iron accumulation (type 1 refers to NBIA produced by PKAN deficiency whereas type 2 is due to PLA2G6 deficiency or PLAN: PLA2G6 associated neurodegeneration); NTE: neuropathy target enterase deficiency; PANK2: pantothenate kinase 2 deficiency; PLA2G6: phospholipase A2 deficiency. PVWMH: periventricular White matter hyperintensities; SLS: Sjöegren Larsson syndrome; SN: substantia nigra.

Severe early hypotonia and muscle weakness with sensory and autonomic neuropathy associated

  with global hypotrophy, developmental retardation, vocal cord paresis, anhydrosis, cataract, and severe respiratory problems.

	Serine	AD. Genes:	Dick 1993
	palmitoyltransferase (corresponding to common (SPT) is the most	and DNMT1 ATL1, RAB7A SPTLC1, SPTLC2,	Rotthier, et al. 2012
	SPTLC1 and SPTCL2
	genes)
		SPTLC1 and SPTLC2,unknown inheritance, de novo, isolated	Murphy et al, 2013. Shu et al, 2013, 2014
	Mutation p.S331 at SPTLC1 is associated with a very	cases
	severe phenotype.

Table

  Click here to download Table: Table 2 rev peripheral neuropathy.docx

	SKELETAL AND	AGE AT	quadriparesis with cognitive decline, demyelinating (and MAJOR ASSOCIATED SYMPTOMS	racemase DEFECTIVE	DEFECTIVE	al, 2000 BIBLIOGRAPHIC
	DEMYELINATING NEUROPATHY CARDIAC MUSCLE involvement RECURRENT RHABDOMYOLISIS, MYALGIA MYOGLOBINURIA,	From early childhood to adulthood Adolescence to adulthood Childhood to adulthood ONSET Childhood (2-7 years)	Refsum disease characterized by retinitis pigmentosa, anosmia, variable combinations of polyneuropathy (but mostly demyelinating), deafness, ataxia, and ichthyosis. motor) polyneuropathy may also be present. Adrenomyeloneuropathy: although the spinal cord involvement and SP are the most prominent signs, axonal and/or demyelinating neuropathy are frequent. -SP that may associate ataxia and hypogonadism Adrenomyeloneuropathy: involvement of long ascending and descending tracts of the spinal cord , progressive SP, usually associated with peripheral neuropathy. Adrenal insufficiency. Axonal and/or demyelinating neuropathy are Frequent episodes of myoglobinuria, lasting from 7 to 10 days and induced by infections, febrile illnesses, fasting or -SPG26: SP that may associate cognitive impairment, cerebellar ataxia, dystonia, muscle wasting, axonal mild learning disability has been reported in one patient, and The central nervous system is usually non affected, however, frequent anesthesia. Between episodes patients are asymptomatic.	Phytanoyl-CoA hydroxylase (>90% of patients) ALDP deficiency Neuropathy target enterase (NTE) ENZYME ALDP deficiency Phosphatidate-phosphatase-1 GM2 synthase deficiency (Lipin 1)	PHYH (AR) PNPLA6 (AR) GENE (Inheritance) ABCD1 (X-linked) LPIN1 (AR) ABCD1 (X-linked) Steinberg et al, Wanders et al, 2006, 2010 Synofzik et al, 2014, REFERENCES Steinberg et al, Zeharia et al, 2012 2008. Michot et 2012 2013; Harlalka et B46ALNT1 (AR) Boukhris et al, al, 2010
	Late childhood AXONAL NEUROPATHY Infantile to adulthood childhood Abbreviations: Childhood to	decremental EMG Response neuropathy and psychiatric signs. Normal brain MRI. generalized muscle hypotonia at age 18 months, has been Racemase deficiency is mostly associated with sensory-motor neuropathy reported in another case. -SP and cognitive regression. Symptoms such as hearing renal cysts may be present. of the anterior horn cell. Patients showed fatigability and neurogenic changes, suggesting that pathology is at the level impairment, facial dysmorphism, hepatic involvement and Electrophysiology and electromyography studies reveal normal motor and sensory conduction velocities with beta oxidation defects may also be present. reduced compound-motor-action-potential amplitudes and characteristic. Other symptoms characteristics of fatty acid Retinopathy and sensory motor neuropathy are also Associated with Spastic Paraparesis (SP) -dHMN: distal hereditary motor neuronopathy. HMN-VII. Episodes of rhabdomyolisis and myalgia may appear.	PTS2 receptor (<10% of patients Racemase: α-Methyl-acyl-CoA-racemase related to PBD Different proteins Presynaptic choline transporter (CHT) TFP LCHAD	PEX7 (AR) AMACR (AR) PEX genes (AR) SLC5A7 (AR) HADHA/B (AR HADHA (AR)	al, 2013 Ferdinandusse et al, 2000; Smith et al, 2010 2012 Waterham et al, 2012 Barwick et al, Olpin et al, 2005
		Adulthood	Recurrent rhabdomyolisis and stroke like episodes has been	Racemase: α-	AMACR (AR)	Kapina et al, 2010
	MYOPATHY (muscular dystrophy, weakness,	Childhood Infantile	Refsum -like: PHARC syndrome: demyelinating polyneuropathy, hearing loss, ataxia, retinitis pigmentosa. Other symptoms that may appear: ataxia, ID, myoclonic seizures. described in a single patient. Sensory motor neuropathy and other Refsum-like symptoms have been described in several -Severe sensory motor polyneuropathy with spastic Associated with retinopathy and episodes of patients. paraparesis, abnormal gait, pes equinovarus and borderline intelligence. Brain MRI: CC and cerebellar hypoplasia ( 1 single case described) rhabdomyolysis. Other symptoms characteristics of fatty acid beta oxidation defects may also be present Severe myopathic phenotype at birth that gradually	α/β-Hydrolase 12 Methyl-acyl-CoA-racemase Arylsulfatase family member 1 LCHAD TFP 3-hydroxyacyl-	ABHD12 (AR) ARSI (AR) HADHA (AR) HADHA/B (AR) PTPLA (AR)	Eisenberg et al, 2012; Fiskerstrand et al, 2010 Novarino et al, Olpin et al, 2005 2014 Smith et al, 2010 Muhammad et al,
	elevated CK)	to adulthood Adolescence	X-linked adrenoleukodystrophy: although the most prominent findings are cerebral demyelination associated with a severe neurological regression and progressive spastic symptoms found in Refsum disease (see above) towards normal gait and residual pes cavus at adult age. table that refers to central nervous system involvement) As a single clinical manifestation or associated with motor milestones, positive Gower sign. One patient evolved -Other causes of sensory motor neuropathy and SP : PLA2G6, CYP2U1 (SPG56), GBA2 (SPG46) and B4GALNT1 (SPG26) (see Later on: facial weakness, decreased muscle tone, delayed tendon reflexes, weak cry, recurrent apnea of newborn. Improves. Early infantile: severe hypotonia, absent deep	ALDP deficiency Racemase: α-Methyl-acyl-CoA-(HACD1) CoA dehydratase 1	ABCD1 (X-linked) AMACR (AR)	Ferdinandusse et 2012 Steinberg et al, 2013

AR: autosomal recessive. AD: autosomal dominant. CHT: choline transporter. dHMNs: distal hereditary motor neuronopathies. HSAN: inherited sensory and autonomic neuropathy. HSAN1, OMIM#605712 and #605713. ID: Intellectual disability. LCHAD: long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. NTE: neuropathy target enterase deficiency. PBD: peroxisomal biogenesis disorders. SP: spastic paraparesis. SPT: Serine palmitoyltransferase. TFP: trifunctional protein deficiency

Table

  Click here to download Table:Table3rev Muscle and cardiac symptoms JMS_FM-1.docx

	Infantile to childhood Smith Lemli Opitz syndrome (AR) (DHCR7) (incidental) Chanarin-Dorfman syndrome: Myopathy (elevated CK), liver steatosis with hepatomegaly, ataxia, neurosensory hearing loss, cataracts, nystagmus, strabismus and ID with icthyosis.. may be associated. -Early-onset seizure, ichthyosis, hypotonia with elevated CK, +	Alpha/beta hydrolase 5 (ABHD5) MPDU1	ABHD5 (AR) MPDU1 (AR)	Lefèvre et al, 2001 Schenk et al.,
			Intracellular accumulation of triacylglycerol droplets in global developmental delay, failure to thrive and recurrent			2001
			tissues vomiting. Brain MRI revealed generalized atrophy.
	PRIMARY CARDIAC		Dilated cardiomyopathy
	PRESENTATIONS	Infantile Infantile	Sengers syndrome: skeletal myopathy, hypertrophic Primary cardiac presentation without	AGK: acylglycerol IEM of the dolichols.	AGK (AR) DK1 (AR)	Kapusta et al,
			cardiomyopathy, congenital cataract and lactic acidosis. seizures, dysmorphic features, ichthyosis or intellectual	kinase All lead to		2012
	MYOPATHY (muscular	Infantile	Early.onset muscle wasting, mental retardation and abnormal Mental development is normal but patients may day from disability. Dilated cardiomyopathy that leads to life-	Choline kinase beta hypoglycosylated	CHKB (AR)	Mitsuhashi et al,
	dystrophy, weakness,		mitochondrial morphology (enlarged mitochondria). Some early cardiomyopathy. In the severe neonatal form, abnormal threatening dysrhythmias, persistent transaminase elevations	(CHKB) deficiency target proteins and		2011
	elevated CK)		patients may have dilated cardiomyopathy and seizures basal ganglia, brainstem and cerebellar hypoplasia as well as with decreased Factors XI and ATIII, and microcytic anemia,	belong to the CDG
	+/-CARDIOMYOPATHY		cortical infarction have been reported. Abnormalities of and the ensuing neutropenia.	syndromes.
			mitochondria and storage of glycogen and lipids are found in
			skeletal and cardiac muscle.
		Infantile Any age, Infantile antenatal to adulthood	Barth syndrome: the classical presentation includes Severe hypotonia with elevated CK, seizures and other Encephalomyopathy with: cardiomyopathy, skeletal muscle weakness, neutropenia and associated signs +/-cardiomyopathy -Weakness, hypotonia, mental retardation (COQ3) growth retardation. Cardiomyopathy is the most severe	IEM of the dolichols. Cardiolipin (CL) All lead to Coenzyme Q10 hypoglycosylated deficiencies	TAZ (X-linked) COQ3, COQ9, COQ2 (AR)	Bione et al, 1996 Barth et al, 2004; Clarke et al. 2013
			-With hypertrophic cardiomyopathy and renal tubulopathy presentation (biventricular dilatation or left-ventricular non-	target proteins and
			(COQ9) compactation are the initial signs). Excretion of 3-	belong to the CDG
			-With hypertrophic cardiomyopathy and complex methylglutaconic acid is characteristic but not constant.	syndromes.
			encephalopathy (MELAS-like) (COQ2)
		Infantile Adulthood	-Severe hypotonia with elevated CK, intractable seizures, Hypertrophic cardiomyopathy ichthyosis with loss of hair, severe liver dysfunction and progressive dilated cardiomyopathy. Mild coagulopathy icthyosis and mild ID may be also present. -Acquired microcephaly, severe hypotonia with elevated CK, and early-onset myoclonic epilepsy and cerebellar hypoplasia elevated transaminases and low ATIII mild ID, muscular Myopathy and cardiomyovasculopathy due to neutral lipid Sengers syndrome: described above. Important to highlight storage disease (NLSD) or triglyceride deposit. Myopathy is that the clinical course is dominated by the cardiac problems mostly proximal (although distal predominance is also dilated or hypertrophic. Muscle biopsies shows lipid neonatal onset form. girdle to upper arm, and paraspinal. Cardiomyopathy may be receiving heart transplantation in childhood to a fatal muscles are posterior compartment of leg, shoulder form with survival into the fourth decade, over patients possible), may be asymmetric and frequently-affected and is variable, ranging from a late onset chronic progressive	DK1 DPM 1-3 Patatin-like phospholipase AGK: acylglycerol domain-containing 2 kinase	DK1 (AR) DPM1-3 (AR) PNPLA2 (AR) AGK (AR)	Lefeber et al., 2011 Mayr et al, 2012; Sengers et al, 1975.
			dystrophy. Stroke-like episodes and dilated cardiomiopathy accumulationand rimmed vacuoles. Comorbidities such as

Large and variable spectrum of congenital anomalies including distinctive facial features, microcephaly, intellectual disability, behavioral problems, malformations of the heart, lungs, kidneys, gastrointestinal tract, and genitalia.

				Waterham et
				al, 2006
	Conradi Hunermann linked) syndrome (dominant X-	+	ichthyosiform erythrodermia X-linked dominant chondrodysplasia type II (asymmetric rhizomelic shortening, epiphyseal calcific stippling) with	Waterham et al, 2006
	(EBP)
	Mevalonate kinase deficiency (classic form)(AR) (MVK)	+ (incidental)	RP may be isolated (incidental)

Multisystemic disease with recurrent inflammatory crisis, hepatosplenomegaly, lymphadenopathy and recurrent severe anemia Clinical evaluation of 3 Dutsch patients diagnosed as classic form of RP showed variable extra-ocular symptoms (recurrent childhood febrile crises , mild ataxia , and renal failure). All 3 affected individuals showed a low MK activity and high levels of urinary mevalonic acid (Siemiatkowska 2013) Siemiatkowska et al, 2013 Cerebrotendinous xanthomatosis (AR) (CYP27A1) + Neonatal jaundice, diarrhea, mental retardation, late infantile cataract, Late onset tendon xanthomata (2 nd decade), progressive neurological dysfunction (spastic paraplegia, ataxia), psychiatric symptoms Berginer et al, 1984 Fatty acid elongase (AR) (AD) (ELOVL4) + recessive Stargardt type Iii dominant Congenital ichthyosis and neurological symptoms resembling Sjögren-Larsson disease (Aldamesh 2011) Heterozygous ELOVL4 mutations display an autosomal dominant juvenile form of isolated macular degeneration (Zhang et al 2001) Zhang et al, 2001 Sjogren Larsson (AR)

	PHARC syndrome (AR) (ABHD12)	+	RP may be isolated
	( ALDH3A2)	+ may be	RP	Hypertrophic cardiomyopathy, myopathy, lactic acidosis, 3-methylglutaconic acid excretion (Willemsen 2001)	Willemsen et al, 2001
		isolated
	Refsum disease (AR) (PHYH)	+	RP cardinal sign	ichthyosis Retinitis pigmentosa, cerebellar ataxia, chronic polyneuropathy, sensorineural hearing loss, anosmia, skeletal malformations,	Wanders et al, 2011

Cataract, hearing loss and predominantly demyelinating peripheral neuropathy. RP develops in the second or third decade. RP may be isolated. (Wotrmann this issue) Nishiguchi et al, 2014

	PZO Biogenesis defects (AR)	+	RP	OA	Various phenotypes ranging
	(several PEX)

from typical Zellweger syndrome to neonatal ALD, infantile Refsum disease and late onset polyneuropathy resembling Charcot Marie Tooth disease Wanders et al, 2011

	Phospholipase A2 group V	Benign fleck	Benign yellow-
	(AR)	retina
	(PNPLA5)

white retinal lesions or flecks with otherwise normal retinal findings (Sergouniotis 2011)

			Sergouniotis et
			al, 2011
	Retinal pigment epithelium-	AR RP	LCA,
	65 kD protein isomerase (RPE65)	AD RP LCA

recessive RP, and dominant RP with choroidal involvement (Hanein S et al 2004) Hanein et al, 2004 ABCA4 transporter of the retinal phospholipid compound, N-retinylidene- phosphatidylethanolamine AR Stargardt AR CRD AR RP 19 CRD individuals experience severe loss in visual acuity and color vision and display significant atrophy of the central retina or macula. This is followed by progressive loss in peripheral vision and night blindness. Unlike typical RP, affected individuals with RP 19 show an early loss in central vision and atrophy of the macula in addition to the characteristic features of RP (Zhang et al 2013) Sparrow et al, 2010 Zhang et al, 1999 PITPNM3, phosphatidylinositol transfer membrane-associated family member 3 AD cone dystrophy Patients display subnormal visual acuity and light sensitivity from childhood. Early signs of macular degeneration then appear with a progressive decrease in visual acuity leading to blindness in early adulthood. ERG testing shows a progressive loss of photoreceptor function restricted to the cones. (Köhn,et al 2007) Köhn et al, 2007

	CYP4V2 (CYP4V2)	Bietti's	BCD
	may have important roles in	crystalline
	eicosanoid metabolism.	dystrophy
	Catalysts of ω-3 and ω-6	AR
	oxidations of polyunsaturated
	fatty acids
	RBP3 , interphotoreceptor	AR RP66	IRBP protein binds and transports retinoids in the	den Hollander
	(IRBP) binding protein		epithelium and photoreceptors (den Hollander 2009) interphotoreceptor matrix between the retinal pigmentary	et al, 2009

is characterized by the presence of yellow-white crystals and/or complex lipid deposits in the cornea and retina, atrophy and degeneration of the retinal pigmented epithelium and sclerosis of the choroidal capillaries. These symptoms progress from visual field constriction to eventual night blindness. BCD is a progressive disease, but patients as young as 16 to 17 years of age have been diagnosed (Nakano et al 2012), Nakano et al, 2012 RBP 4 (serum retinol binding protein) (AR) RP Affected siblings had no detectable serum RBP, one sixth of normal retinol levels, and normal retinyl esters. The retinal pigment epithelium was severely affected, but there were no changes to other organs. This gives evidence for an alternative tissue source of vitamin A, presumably retinyl esters from chylomicron remnants (Seeliger MW et al 1999) den Hollander et al, 2009 Seeliger et al, 1999

	Lecithin retinol	RP	Recessive RP, severe early-onset; recessive LCA (Thompson	Thompson et
	acyltransferase (AR)	LCA	2001)	al, 2001
	(LRAT)
	RDH11 (AR)
	RDH11 protein is

a widely- expressed enzyme with a role in oxidizing 11-cis-retinol to 11-cis-retinal similar to RDH 1,5 and 12 RP syndromic RP with facial dysmorphology, developmental delay, and short stature; RP-associated ophthalmological findings included salt- and-pepper retinopathy, attenuation of the arterioles and generalized rod-cone dysfunction with almost extinguished electroretinogram ( Xie et al 2014) Fingert et al, 2008 Xie et al, 2014 RDH12 (AR and AD) 11-cis retinol dehydrogenase 12 AR LCA with severe childhood retinal dystrophy; AD RP Symptoms include severe progressive rod-cone dystrophy and macular atrophy; may account for 4% of recessive LCA (Fingert et al 2008, Perrault et al 2004) Perrault et al, 2004

	RDH5 (AR)	Cone
	11-cis retinol dehydrogenase 5	dystrophy, late onset
	(same pathway as in RDH11
	and 12)
		Yamamoto et
		al, 1999

Stationary night blindness with subretinal spots and delayed dark adaptation; extremely delayed rod and cone resensitization in null mutation (AV Cideciyan et al 1999, H Yamamoto et al 1999) Cideciyan et, 1999 Ceramide kinase like(AR) (CERKL) RP non syndromic Primary dysfunction or loss of cone photoreceptors and then of rod photoreceptors. Patients present with a progressive loss of central vision, visual field constriction and nyctalopia. (Aleman TS 2009) Aleman et al, 2009 Dehydrodolichyl diphosphate synthase (AR) (DHDDS) RP non syndromic DHDDS K42E and T206A missense mutations have been linked to non syndromal RP( Züchner S et al 2011, Zelinger L et al 2011) Zelinger et al, 2011 Züchner et al, 2011 Joubert syndrome (AR)

	RP	Absence or underdevelopment
	(INPP5E, encoding inositol
	polyphosphate-5-phosphatase
	E)

of the cerebellar vermis and a malformed brain stem (molar tooth sign). Most common features include ataxia, hyperpnea, sleep apnea, abnormal eye and tongue movements, and hypotonia., with variably associated retinitis pigmentos, nephronophthisis,liver fibrosis and polydactyly .It is included in the newly emerging group of 'ciliopathies' (Bielas 2009) Bielas et al, 2009

	Phosphocholine citidylyl	CRD	Spondylometaphyseal dysplasia,
	transferase (AR)
	(PCYT1A)

short stature with rhizomelia, platyspondyly, early-onset visual impairment with pigmentary maculopathy and cone-rod dysfunction (Wortmann this issue)

	Tocopherol carrier deficiency	RP	Cerebellar ataxia and sensory neuronopathy sometimes	Pang et al, 2001
	(AR) (TTPA)		associated with cardiomyopathy and retinitis pigmentosa. Resembles Friedreich ataxia.
	Dolichol synthesis (AR)	OA	Developmental delay, ataxia and early visual impairment with	Millon et al,
	(DHDDS) (SRD5A3)		dysfunction (Lefeber this issue) optic atrophy, occasional ichthyosiform dermatitis and liver	2011
	Dolichol recycling (AR)	OA	DPM1phenotype :
	(DPM1 : CDG1e)
	(MPDU1 :CDG 1f)	OA
				Yamamoto et
				al, 2014
	Boucher-Neuhauser	RP	Ataxia with cerebellar atrophy, chorioretinal degeneration,
	syndrome (AR)		hypogonadotropic hypogonadism (Wortmann this issue)
	(PNPLA6)

acquired microcephaly, dysmorphic facial features, visual loss with optic atrophy, frontal cortical atrophy and delayed myelination, intractable seizures, hypotonia with elevated CK . MPDU1 deficiency : early onset nystagmus and optic atrophy with early visual loss together with early-onset seizures, ichthyosis, hypotonia with elevated CK, global developmental delay, failure to thrive and recurrent vomiting (Lefeber this issue) Lefeber et al, 2011 Amish epilepsy syndrome (AR) (ST3GAL5) OA Early severe epileptic encephalopathy, pharmacorresistant, with developmental delay and blindness (Levade this issue) Fragaki et al, 2013

TABLE 4

 4 Ophtalmological presentations

	Abbreviations: AR: autosomal recessive; AD: autosomal dominant; LCHAD: 3-hydroxy long chain acyl CoA dehydrogenase; PZO: Peroxisome; RP: retinitis
	pigmentosa; LCA: Leber congenital amaurosis; CRD: cone rod dystrophy; OA: optic atrophy

OA The onset is typically between 4 and 20 years of age, and the progression is generally slower than PKAN and INAD. The clinical presentation comprises dysarthria and gait difficulties followed by spasticity, dystonia, parkinsonism, psychiatric symptoms, motor axonal neuropathy and optic atrophy. MRI: T2 hypointensities in pallida and substantia nigra Tiranti this issue

	Infantile neuroaxonal	OA	Motor and mental
	dystrophy (INAD)
	(AR)
	(PLA2G6)

deterioration, cerebellar ataxia, marked hypotonia, spastic tetraplegia, and early visual disturbances. MRI: T2 hypointensities in pallida and substantia nigra

		Tiranti this
		issue
	Phospholipase A1 (AR) (DDHD2)	+

Optic nerve hypoplasia Early onset spastic paraplegia, strabismus, dysarthria ± dysphagia, developmental delay. MRI: thin corpus callosum, abnormal NMR lipid peak on MRS Wortmann this issue Charcot-Marie-Tooth Disease associated with early-onset glaucoma (AR) (SBF2) Glaucoma Demyelinating CMT, mainly characterized by myelin outfoldings on nerve biopsies, and early-onset glaucoma. MTMR13 is involved in phosphoinositide metabolism

	MAIN SYMPTOM	AGE AT ONSET	MAJOR ASSOCIATED SYMPTOMS	DEFECTIVE	DEFECTIVE GENE	REFERENCES
				ENZYME	(Inheritance)
	ICHTHYOSIS	Congenital to early	Non syndromic autosomal recessive congenital
	(ARCI)	infantile	ichthyosis (ARCI)
		<4months
			-ABCA12 lipid transporter defects may present with
			Harlequin ichthyosis (HI), congenital ichthyosiform
			erythroderma (CIE) or lamellar ichthyosis type 2 (LI). LI
			patients are born as collodion babies and present a
			generalized lamellar ichthyosis with large adherent dark
			pigmented scales, with ectropion and palmoplantar
			keratoderma.
						Azzedine 2003

Table

  Click here to download Table: Table 5 Rev Skin final_FM.docx

TABLE 5

 5 Dermatological presentations

	Abbreviations:
	AR: autosomal recessive; AD: autosomal dominant; ARCI: autosomal recessive congenital ichthyosis. DD: Developmental delay; ELOVL: elongase/elongation
	of very long chain fatty acids deficiency. FALDH: Fatty aldehyde dehydrogenase deficiency. GPI: glycosylphosphatidylinositol. HSP: hereditary spastic
	paraparesis; SLS: Sjögren-Larsson syndrome.

Bone involvement is an important concern in late childhood to adulthood. Medullary infarction of long bones may cause excruciating pain ("bone crisis"). Aseptic necrosis of femoral head and spontaneous fractures due to osteopenia are common findings and can be inaugural.

	Glucocerebrosidase	GBA	Vanier 2012
	type 1
	Phosphocholine
	Citidylyl transferase
	deficiency (AR)

Spondylometaphyseal dysplasia (short stature with rhizomelia, platyspondyly, metaphyseal irregularity, bowing of long bones) with cone-rod dystrophy.

	Phosphocholine	PCYT1A	Wortmann
	citidylyl transferase		this issue
	(alpha isoform)
	Lenz Majewski
	hyperostotic dwarfism
	syndrome (AD)

Progressive generalized hyperostosis leading to severe growth restriction, typical craniofacial dysmorphic features (thickness of the jaw, clavicles and ribs), distal- limb abnormalities (proximal symphalangism), cutis laxa, intellectual disability.

	Phosphatidylserine	PTDSS1	Wortmann
	synthase 1		this issue
	gain-of-function
	Opsismodysplasia

(AR) Chondrodysplasia characterized by pre-and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, extreme delayed skeletal ossification and metaphyseal cupping. Inositol polyphosphate phosphatase-like 1

	INPPL1	Cormier-Daire
		2003
		Huber 2013
		Below 2013

Table

  Click here to download Table:Table6Rev Bone lipids JMS_FM2-1-3.doc

SHORT syndrome (AD) Short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly and teething delay.

			Phosphoinositide	PIK3R1	Thauvin-
			kinase (PIK)		Robinet
					2013
	Phosphoinositide	Megalencephaly, polymicrogeria, polydactyly,	Phosphoinositide	FIG4	Gross 2014
	kinase 3	hydrocephalus syndrome .	kinase (PIK)
	PIK3CA-related	Congenital asymmetric disproportionate overgrowth -
	segmental overgrowth	mild with little
	disorders.
	(Somatic mutations in the
	phosphatidylinositol/AKT/
	mTOR pathway)

postnatal progression in most, severe and progressive requiring multiple surgeries in others. Overgrowth affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern. Congenital lipomatosis is present in all patients and, in the most severely affected patients, is associated with marked paucity of adipose tissue in unaffected areas.

	PIK3CA	Keppler-
	(somatic	Noreuil
	mutations)	2014
	Rhizomelic
	chondrodysplasia
	punctata (RCDP)
	type I-

II-III (AR) Severe proximal shortening of limbs, facial dysmorphism, cataracts, calcific stippling of epiphyses, coronal clefts of vertebral bodies, multiple joint contractures, growth and psychomotor delays, ichthyosis. The chondrodysplasia punctata may involve extra-skeletal tissues.

	PTS2 (type I)	PEX7	Poll The 2012
	DHAPAT (type 2)	GNPAT
	Alkyl-DHAP synthase	AGPS
	(type 3)

Patients (girls) with short stature, asymmetric rhizomelic shortening of the limbs, calcific stippling of the epiphyseal regions and craniofacial defects. Associated with ichthyosiform erythroderma in the neonate, atrophic and pigmentary lesions in childhood, and coarse lusterless hair and alopecia in adults, and cataracts.

						Skjeldal
						1987
	Conradi-Hünermann	Sterol 	8 -	7	EBP	Waterham
	(X-linked dominant) (CDPX 2)	isomerase			2006 Braverman 1999
						Derry 1999

Variable spectrum of morphogenic and congenital anomalies: characteristic craniofacial appearance and limb abnormalities including cutaneous syndactyly of the 2 nd and 3rd toes, postaxial polydactyly and short proximally placed thumbs.

	7-dehydro	DHCR7	Waterham
	cholesterol		2006
	reductase
	Desmosterolosis (AR)

Short limb, osteosclerosis, dysmorphic facial features, microcephaly, profound developmental delay and brain malformations including agenesis of the corpus callosum.

						3-hydroxysterol	DHCR24	Waterham
							24 -reductase	2006
	Lathosterolosis (AR)	Only two patients reported who presented at birth with	sterol 	5 -desaturase	SC5D	Waterham
		postaxial	hexadactyly,	syndactyly,	craniofacial		2006
		dysmorphism, severe microcephaly and SLOS-like
		features.
	Greenberg skeletal
	dysplasia
	(AR)

Severe fetal hydrops, short-limb dwarfism, unusual 'moth- eaten' appearance of the markedly shortened long bones, bizarre ectopic ossification centers and marked disorganization of chondro-osseous histology. May present with polydactyly and non skeletal malformations (HEM skeletal dysplasia) 3-hydroxysterol sterol  14 -reductase LBR Waterham 2006

TABLE 6

 6 Orthopedic presentations

	Abbreviations:
	AR: autosomal recessive; AD :autosomal dominant;;PZO :Peroxisome

Table

  Click here to download Table:Table7Rev liver JMS-FM-2.docxCerebrotendinous xanthomatosis (CTX)Cholestatic jaundice in infancy may be the first manifestation of CTX . However, it usually improves spontaneously. The next (or the first) symptom of CTX is often psychomotor delay detected during the first decade of life.

TABLE 7 Hepatic presentations Hepatic steatosis

 7 Early infantile Chanarin-Dorfman Syndrome Congenital erythrodermic ichthyosis, hepatomegaly with liver steatosis (70%), nystagmus, cataracts, decreased hearing, mental retardation, myopathy, non-lysosomal lipid storage disease .Tissular accumulation of neutral lipids (vacuoles). Neutral lipid storage with myopathy of proximal and distal muscles, asymmetric muscle atrophy, hepatomegaly and liver steatosis (50%).

	Berardinelli Seip Syndrome. Congenital generalized lipodystrophy
	Striking muscular appearance, hyperinsulinemia (insulin resistance),
	hypertriglyceridemia, accelerated growth, hepatomegaly with liver
	steatosis.
	Triglyceride lipase deficiency. Glycerol-3-

phosphate dehydrogenase deficiency Early

  infantile moderate to massive hepatomegaly and steatosis, abnormal liver function tests, transient infantile hypertriglyceridemia ,and development of hepatic fibrosis. Normal neurologic examination. One patient with microcephaly. Late childhood presentation with severe nonalcoholic fatty liver disease, low HDL cholesterol levels, lipodystrophy, severe insulin resistance, diabetes and short stature without any spondylometaphyseal dysplasia and visual impairment (no cone-rod retinal dystrophy).

	domain containing 5 1-acylglycerol-3-phosphateO-acyltransferase Patatin-like Phospholipase Glycerol-3-phosphate dehydrogenase 1 Phosphate cytidylyltransferase 1 alpha deficiency. a/b-hydrolase Phosphate	ABHD5 AGPAT2 PNPLA2 GPD1 PCYT1A	Mitchell this issue Mitchell this issue Mitchell this issue Basel-Vanagaite 2012 Joshi 2014 Mitchell this issue Payne 2014
	cytidylyltransferase
	1 alpha

Sengers et al, 1975; Mayr et al, 2012. Salviati et al, 2005, 2012 Duncan et al, 2009, Jackobs et al, 2013 Kaneko et al,

Acknowledgments

We acknowledge Dr Hans Mayr for the supplementary table "Gene defects in the lipid metabolism and their predominant clinical manifestation".

TABLE 3 Muscular and cardiac symptoms

Abbreviations:

ABDH5: Alpha/beta hydrolase 5. AR: autosomal recessive. AD: autosomal dominant. CL: Cardiolipin. ID: Intellectual disability. HSAN: inherited sensory and autonomic neuropathy. CK: Creatine Kinase. HACD1: 3-hydroxyacyl-CoA dehydratase 1. DPM; dolichyl-phosphate-D-mannose: protein O-D-mannosyltransferase. ID: Intellectual disability. MPDU1: Mannose-P-Dolichol Utilization Defect 1. NLSDM: neutral lipid storage disease miopathy. NTE: neuropathy target enterase deficiency. PNPLA2: Patatin-like phospholipase domain-containing 2. SP: spastic paraparesis. SPT: Serine palmitoyltransferase.