| I COMPLEX MOLECULE ACCUMULATION DEFECTS |
In general no antenatal manifestations, although occasionally reported in very severe forms |
Great variety of brain MRI abnormalities that evolve towards progressive cortical/subcortical atrophy |
Progressive disorders with late-onset NDEG with or without obvious “storage” signs (like hepatosplenomegaly, coarse facies, cherry red spot, dysostosis multiplex, vacuolated lymphocytes) |
These disorders are NDEG diseases. Some forms lead to early death. New therapies have been currently developed in order to modify these fatal outcomes |
1 |
| Glycogen (APBD, Lafora disease). NDEG starting in adolescence or adulthood / myoclonic epilepsy syndrome with polyglucosan deposition1
|
| Sphingolipid catabolism: Sphingolipidoses (SPD) are a subgroup of lysosomal storage disorders in which sphingolipids accumulate in one or several organs. Most SPD present with post-natal progressive neurological regression. The clinical presentation and course of the most severe classic forms are often typical. Late-onset less typical forms (with movement disorder or psychiatric presentations) have been overlooked in the past. Diagnosis is mostly based on leukocytes, enzymes, and molecular analysis45
|
| Gaucher type 2 (B cerebrosidase) |
|
Brain atrophy |
Acute neuronopathic perinatal form |
Early death |
45 |
| Gaucher type 3 |
|
Brain atrophy |
Myoclonic epilepsy, brainstem dysfunction starting at 5-8 years of age |
In general, these disorders start with arrest of neurodevelopment in early forms and with learning disabilities in older children following by motor signs (ataxia, spasticity) and other neurological symptoms leading to a progressive NDEG Age at death ranges from childhood to adulthood depending on the age of first symptoms |
45 |
| Niemann-Pick Disease type A (ASMD) |
In general, no antenatal brain abnormalities are found in these diseases |
Brain atrophy |
At 5-10 months: hypotonia, loss of acquired motor skill, intellectual deterioration, spasticity, rigidity. Death below 3 years |
|
45 |
| Niemann-Pick Disease type C (NPC1/2) |
|
Cerebellar atrophy |
- Early infantile: regression, spasticity - Late infantile: ataxia, MD, spasticity - Adult: ataxia, MD, psychiatric signs |
|
45 |
| Gangliosidosis GM1 (late onset) GM2 |
|
Basal ganglia abnormalities, cerebellar atrophy |
- Rapid regression, seizures, spasticity - Late infantile: ataxia, seizures - Adult: ataxia, MD, psychiatric signs |
|
45 |
| Krabbe disease |
|
WM lesions, calcifications |
Rapid global regression in early forms. Gait disturbances, optic atrophy, later forms |
|
45 |
| Metachromatic leukodystrophy |
|
Characteristic leukodystrophy |
Spastic tetraparesis, optic atrophy Late-onset: motor and/or psychiatric signs |
|
45 |
| Neuronal ceroid lipofuscinosis (NCL) Group of disorders with accumulation of autofluorescent ceroid lipopigments in neural tissue. Diagnosis is mostly based on molecular analysis. They are usually characterized by progressive psychomotor retardation, seizures, visual loss, and early death. Initial signs and outcome depend on the different subtypes: Congenital forms (Cathepsin D), Infantile NCL (6-24 months). Late infantile NCL (2-4 years). Juvenile NCL (4-10 years); Adult NCL (30 years)45
|
| INCL, LINCL, JNCL, ANCL |
Severe cortical/ subcortical atrophy may be present at prenatal stages in the congenital form |
Cerebellar atrophy may be the initial sign followed by global, progressive brain atrophy |
- Congenital: early death -INCL-CLN1: Microcephaly, optic atrophy, ataxia, myoclonus, regression -LINCL-CLN2: Jansky Bielschowsky. Seizures, ataxia, regression - JNCL: Batten disease, seizures, dysarthria, parkinsonism, dementia - ANCL: progressive myoclonic epilepsy: type A. Dementia with motor signs: type B |
NDEG: Progressive motor and cognitive decline leading to death. |
45 |
| GAG and oligosaccharide catabolism. Mucopolysaccharidosis (MPS) and oligosaccharidosis are a subgroup of lysosomal storage disorders in which glycosaminoglycans (GAG) or glycoproteins accumulate in one or several organs. Most those disorders display post-natal progressive neurological regression but only a few present with predominant cognitive impairment. Diagnosis is based on GAG analysis and leukocyte enzyme analysis1
|
| MPS type III (Sanfilippo disease) |
In general, no antenatal brain abnormalities are found in these diseases |
Progressive cortical/ subcortical atrophy. Enlarged perivascular (Virchow) spaces are also common |
2-6 years: Learning difficulties with behavioral problems followed by cognitive decline |
NDEG: Progressive motor and cognitive decline leading to death |
1 |
| B mannosidosis Fucosidosis Salla Disease |
|
|
Variable neurodegenerative disorder seizures; learning difficulties, challenging behavior |
In Sanfilippo disease, learning difficulties and NPSY signs mimicking NDEV disorders normally precede NDEG |
1 |
| Sialidosis (MLI) Mucolipidosis (ML IV) |
|
|
Slowly progressive cherry red spot myoclonus developmental delay with progressive blindness |
|
1 |
| II COMPLEX MOLECULE SYNTHESIS DEFECTS |
Antenatal abnormalities found in cholesterol defects and phosphatidylinositide defects |
Diverse post-natal brain abnormalities. Brain and cerebellar atrophy common in NDEG defects |
Great variety of manifestations. Most presenting complex motor problems, although ID and epilepsy are also present |
Most of them NDEG. Only a few mimic NDEV diseases at early stages of the disease |
| Phospholipid synthesis and recycling (PL). A few defects in de novo PL synthesis and many defects of phospholipases involved in the remodeling of lipid membranes display preponderant late-onset neurodevelopment/neurodegeneration presentations. Two defects present with congenital spondylometaphyseal dysplasia or Lenz-Majewski dwarfism39,46
|
| Choline kinase |
In general, antenatal brain abnormalities have not been described in these diseases |
Thin CC (occasional) |
Mimics NDEV disorders with ID and NPSY (ASD) but associates muscle dystrophy, early onset muscle wasting |
All these diseases have a NDEG character. Initially they can mimic CP |
39, 46 |
|
SERAC1
|
|
Characteristic basal ganglia abnormalities |
MEGHDEL syndrome (early dystonia spasticity) dyskinetic CP. Mild late forms |
|
39, 46 |
|
ABHD12
|
|
Cerebellar atrophy |
PHARC syndrome. Demyelinating polyneuropathy, cataracts, hearing loss, and RP mimicking Refsum disease |
|
39, 46 |
|
PLA2G6
|
|
Cerebellar atrophy Pallidum hypointensities due to iron accumulation |
1) Infantile neuroaxonal dystrophy 2) Neurodegeneration with brain iron accumulation. Static encephalopathy 3) Early onset dystonia parkinsonism, cognitive decline, and psychiatric disorder (PARK 14) |
|
39, 46 |
|
PNPLA6
|
|
Cerebellar atrophy |
Clinical spectrum of neurodegenerative disorders: HSP (SPG39), Boucher-Neuhauser, GordonHolmes, Oliver McFarlane and Laurence-Moon syndromes |
|
39, 46 |
|
DDHD1
|
|
ThinCC. WM abnormalities may be present |
HSP (SPG28), cerebellar ataxia without ID |
|
39, 46 |
|
DDHD2
|
|
ThinCC. WM abnormalities may be present |
Progressive complex HSP (SPG54),ID, developmental delay |
|
39, 46 |
|
CYP2U1
|
|
Basal ganglia calcifications |
HSP with basal ganglia calcifications (SPG56) |
|
39, 46 |
| Phosphatidyl inositides (PI3K)/AKT. Phosphatidylinositol are PL synthesized from cytidyl diphosphate diacylglycerol. The PI3Kinases are a family of signaling enzymes that regulate a wide range of processes including cell growth and brain development47
|
|
AKT3, PIK3R2 and PIK3CA
|
Megalencephaly-capillary malformation and megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndromes |
Congenital macrocephaly |
Sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. Mimicking ID and overgrowth syndromes |
Stability. Behave as NDEV disorders |
47 |
| Sphingolipids (SPL): At least 7 SPL synthesis defects display preponderant late-onset neurodevelopment/neurodegeneration presentations including HSP |
| CERS I and II |
In general, antenatal brain abnormalities have not been described in these diseases |
Brain atrophy |
Progressive myoclonic epilepsy and cognitive decline (childhood/ adulthood) |
All these diseases have a NDEG character. Initially they can mimic CP; GM3 synthase may mimic Rett syndrome |
45 |
| FAHN |
|
Cerebellar atrophy, WM lesions, pallidum hypointensity |
Complex HSP (SPG35) starting in childhood |
|
45 |
| GM3 synthase |
|
Initially normal but evolving towards diffuse brain atrophy |
At 3 months: Amish epilepsy syndrome, profound developmental stagnation and regression. Salt and pepper syndrome Rett syndrome-like, mimicking NDEV disorders |
|
45 |
| GM2/GD2 synthase |
|
Brain atrophy |
Slowly progressive HSP with mild to moderate cognitive impairment (SPG26) |
|
45 |
| GBA2 |
|
Cerebellar atrophy |
Adolescence to adulthood: Autosomal recessive cerebellar ataxia and complex HSP (SPG46) |
|
45 |
| Serine palmitoyl transferase |
|
|
Dominant hereditary sensory neuropathy (HSAN12). Starting in adulthood |
|
45 |
| Cholesterol and bile acids: Most cholesterol synthesis disorders may present with various multiple congenital and morphogenic anomalies including brain, and/or a marked delay in psychomotor development. These include Greenberg dysplasia, X-linked dominant chondrodysplasia punctata, lathosterolosis and desmosterolosis, Smith-Lemli-Opitz syndrome, CHILD syndrome, and CKS. Diagnosis is based on plasma oxysterol analysis by GC/MS48
|
| MKD-MA |
|
Cerebellar atrophy |
Autoinflammatory disorder with ID, ataxia, hypotonia, dysmorphic features |
Stability versus mild improvement, they mimic NEURODEV disorders, although long-term outcomes have not been reported |
48 |
| 7-dehydrocholesterol reductase |
Congenital microcephaly may be present |
Microcephaly |
Smith Lemli Opitz syndrome: Facial dysmorphism, poly malformations Mild forms may mimic NDEV disorders: ID, NPSY signs including ASD |
|
48 |
| Sterol Delta8 Delta7 isomerase Hemizygous males |
Dandy-Walker malformations CC agenesis |
Microcephaly |
Facial dysmorphism. ID and NPSY signs mimicking a NEURODEV disease |
|
48 |
| NSDHL (X-linked) Hemizygous males |
Cortical malformations, congenital microcephaly |
The same abnormalities as at prenatal stages |
CK syndrome: facial dysmorphism. Poly malformations, mild to severe ID, seizures beginning in infancy, NPSY signs including aggression, and ADHD |
|
48 |
| III PEROXISOME DISORDERS |
Many peroxisomal disorders interfere with fetal neurodevelopment |
Cerebellum and white matter are often affected |
Severe early-onset encephalopathies with multisystem involvement and late onset presentations |
In general they have a neurodegenerative outcome |
49 |
| Plasmalogen synthesis defects: Of the 5 types known so far only the fatty acyl-CoA oxido reductase 1 that involves the fatty cohol cycle presents with isolated severe neurological dysfunction |
| RCDP types 1-4 |
Cerebellar atrophy |
The same abnormalities as at prenatal stages |
Mostly severe skeletal dysplasia, (RCDP), facial dysmorphism Severe ID, cerebellar atrophy, seizures |
May mimic NDEV disorders as complex malformative syndromes but may evolve towards NDEG |
49 |
| Fatty acyl-CoA oxido-reductase |
Dandy Walker variant |
The same abnormalities as at prenatal stages |
No RCDP. Severe ID, earlyonset epilepsy, microcephaly, congenital cataracts, growth retardation, and spasticity |
|
49 |
| Peroxisomal β-oxidation: PZO plays an indispensable role in the oxidation of VLCFA, pristanic, bile acids, and eisosanoids the deficit of which causes severe neurological deficits |
| Peroxisome biogenesis defects (>12 PEX defects |
Cortical dysplasia, neuronal heterotopias, polymicrogyria pachygyria, periventricular cysts |
Dysmyelination, demyelination, cerebellar atrophy |
ZW spectrum disorders: 1) Classic ZW: Severe psychomotor retardation, profound hypotonia, seizures, deafness, RP 2) Many variants forms as NALD or IRD with overlapping symptoms; 3) Very mild forms with unspecific ID or cerebellar ataxia |
Stability later on evolving towards NDEG |
49 |
| Isolated FA oxidation enzyme defects: Of these only the D-bifunctional protein (DBP) may interfere with antenatal development and mimics classic ZW |
| X-ALD (male) AMN (male and female) |
Not reported |
Demyelination |
Childhood cerebral form leading to vegetative state and early death Adult progressive spastic paraparesis |
X-ALD may mimic initially ADHD and other NPSY signs later on evolving towards NDEG |
49 |
| 1. DBP 2. Acyl CoA oxidase 3. Racemase 4. Phytanyl-CoA hydroxylase |
Not reported |
Demyelination, Cerebellar atrophy |
1 - ZW like, Perrault syndrome or late onset neurodegeneration 2 - Neonatal adrenoleukodystrophy phenotype, mild ZW 3 - Mild forms mimic Refsum disease relapsing encephalopathy 4 - Adult Refsum disease: progressive polyneuropathy with RP and deafness |
These disorders evolve towards NDEG |
49 |
| IV CONGENITAL DISORDERS OF GLYCOSYLATION |
Many disorders interfere with neurodevelopment in fetal life |
Cerebellar involvement is very common and may be progressive at the brain MRI with no clinical translation51
|
CDG should be considered in any unexplained clinical condition particularly in multiorgan disease with neurological involvement but also in nonspecific ID |
Some forms (O-glycosylation and COG6) lead to early death. Most forms have stable/mild improvement outcome |
50 |
| Congenital disorders of protein O-Glycosylation: Major symptoms involve brain, eye, skin, skeleton, cartilage and skeletal muscles in variable combination. Among the >10 defects involving the brain two are responsible for neuronal migration disorders. Screening methods: serum apolipoprotein C-lll isoelectrofocusing |
| Cerebro-ocular -muscular dystrophy syndromes (POMT1/2 -CDG)
|
Cobblestone lissencephaly, cerebellar hypoplasia. Hydrocephaly, encephalocele CC agenesis |
The same abnormalities as at prenatal stages |
Absent psychomotor development Congenital muscular dystrophy Brain, eye dysgenesis |
Early death (<1y) |
50 |
| Muscle -eye- brain disease POMGNT1 CDG
|
Same as above |
Same as above |
Same as above but less severe with longer survival |
|
50 |
| Congenital disorders of protein N-glycosylation: Cerebellar involvement is an important feature of PMM2-CDG. It has also been reported in some patients with ALG1-CDG, ALG3-CDG, ALG9-CDG, ALG6-CDG, ALG8-CDG, SLC35A2-CDG (UDP-galactose transporter), B4GALT1-CDG (GM2 synthase). Screening methods are limited to serum transferrin isoelectrofocusing and molecular analysis. |
|
PMM2-CDG
|
Olivopontocerebellar hypoplasia |
Cerebellar atrophy may progress |
1) Alternating internal strabismus, axial hypotonia, developmental disability, ataxia RP. Dysmorphism, fat pads 2) Mild forms: isolated slight ID |
Stability versus mild improvement |
50, 51 |
|
1. ALG6-CDG 2.ALG1-CDG 3. DPAGT1-CDG 4. MAN1B1CDG
|
Stroke, brain atrophy Periventricular lesions CC agenesis (rare) |
|
1- Same as above with skeletal abnormalities. No RP. NPSY signs 2- Severe neurological dysfunction: severe ID, hypotonia, intractable seizures, tremor, ataxia, visual disturbances 3- Moderate/severe ID, hypotonia, epilepsy 4- Mild to severe ID, hypotonia. Abnormal speech development. NPSY signs |
Stability versus mild improvement |
50 |
| Dolichol synthesis utilization/recycling: Cerebellar involvement is a frequent finding in SRD5A3-CDG, DPM1-CDG, DPM2-CDG, COG1-CDG, COG5-CDG, COG7-CDG, and COGS-CDG. |
| SRD5A3-CDG |
Vermis atrophy |
Vermis atrophy |
ID, hypotonia, spasticity, cerebellar ataxia, with ophtalmological symptoms (coloboma,optic atrophy) Diagnosis on serum transferrin (IEF type 1 pattern) |
Stability versus mild improvement |
50 |
| COG6-CDG (CDG+) |
Cerebellar atrophy |
Microcephaly |
Developmental/ID. Liver involvement |
Early death |
50 |
| Lipid glycosylation/GPI synthesis PIGA-CDG. Multiple brain antenatal abnormalities. Multiple congenital anomalies “hypotoniaseizures syndrome” or “Ferro-cerebro-cutaneous syndrome.” Facial dysmorphism. Diagnosis on hyperphosphatasia. |
| N-Glycanase deficiency: IUGR, developmental disability, microcephaly, movement disorder, hypotonia, seizures, alacrimia, liver involvement. |
| V INTRACELLULAR TRAFFICKING/ PROCESSING DISORDERS |
Frequent abnormalities, in particular if the defect is localized at the ER/Golgi/Cytoskeleton |
Very diverse abnormalities |
From severe encephalopathies with multisystem involvement to the “synaptopathy” spectrum signs |
Trafficking and autophagy defects are often related to neurodegeneration |
52, 53, 55 |
| Synaptic vesicle (SV) disorders: Synaptic vesicle disorders have been recently defined as a group of diseases which involve defects in the biogenesis, transport and synaptic vesicle cycle. Clinical signs of synaptic dysfunction include intellectual disability, neuropsychiatric symptoms, epilepsy and movement disorders. Many disorders are involved that overlap many IEM categories. The complexity of this group of diseases is beyond the scope of this article11,32,44
|
| SNARE proteins: SNARE proteins compose a large group of proteins involved in membrane fusion between vesicles and target membranes. Most SNARE deficiencies disturb neurotransmission at the synaptic vesicle level |
|
SNAP29 (CEDNIK syndrome) |
Cortical dysplasia. Pachygyria, polymicrogyria CC hypoplasia |
The same than antenatal |
CEDNIK syndrome: neurocutaneous syndrome characterized by cerebral dysgenesis, early severe ID, microcephaly, ichthyosis, and keratoderma |
Stability |
54 |
| SNARES involved in the SV cycle: NAPB, PRRT, SNAP25, STXBP1, S GOSR2, TX1B...
|
In general, they do not present antenatal brain malformations |
Microcephaly, hypomyelination, cerebellar/cortical atrophy, may be present |
Most present with various types of early onset epileptic encephalopathy with ID, NPSY signs and movement disorders |
These diseases are NDEV disorders. Long-term outcomes have not been reported |
53 |
| SV proteins involved in other SV cycle functions: trafficking, endocytosis. Some of the SNARE proteins participate also in these functions. Patients present with the clinical spectrum of the “synaptopathies” but multisystem diseases with complex neurological disorders including antenatal brain malformations are more likely to appear in trafficking defects between the ER and Golgi. Cortical migration defects are more common if the SV trafficking defect is localized at the axonal and/or dendritic level (involving cytoskeleton) |
|
Rabenosyn-5
|
Not reported |
Microcephaly |
Complex phenotype: early infantile spasms, epilepsy, ID, Vitamin B12 deficiency with MMA accumulation |
Stability |
32 |
|
VPS 15
|
Localized cortical dysplasia (hippocampal) |
The same as antenatal |
Severe cortical and optic nerve atrophy, ID, spasticity, ataxia, psychomotor delay, muscle wasting, pseudobulbar palsy, mild hearing deficit and late-onset epilepsy |
Stability |
32 |
| Autophagy disorders: Clinically, these disorders prominently affect the central nervous system at various stages of development, leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others |
|
AP-5 (SPG 48) |
Thin corpus callosum |
The same as antenatal |
HSP (SPG 48): ID and white matter lesions.. Accumulation of storage material in endoLSD |
These disorders may present initially as NDEV diseases but evolve towards NDEG |
55 |
|
EPG5 (VICI syndrome) |
Non lissencephalic cortical or cerebellar vermis, pons dysplasia, hypoplasia, CC agenesis (constant) often with colpocephaly |
The same as antenatal |
Vici syndrome: multisystem disease. The neurological phenotype is broad and includes progressive postnatal microcephaly, profound developmental delay and ID, motor impairment, nystagmus, sensorineuronal deafness, and seizures |
NDEG |
55 |
|
WDR45 (BPAN: SENDA syndrome) |
Not reported |
May present NBIA features |
BPAN: Childhood: ID, seizures, spastic paraplegia, Rett-like stereotypies, NPSY signs (ASD) Adolescence: progressive dementia, parkinsonism, dystonia, optic atrophy, sensorineural hearing loss |
These disorders may present initially as NDEV diseases but evolve towards NDEG |
55 |
|
SNX14 (Childhood ARCA and ID syndrome) |
Not reported |
Cerebellar atrophy |
Globally delayed development, ID, ASD, hypotonia, absent speech, progressive cerebellar atrophy and ataxia, seizures, and a storage disease phenotype |
|
55 |
| VI t-RNA SYNTHETASES |
Brain antenatal abnormalities may appear |
White matter, cerebellum and brain stem are particularly affected |
Great variety of neurological manifestations often associated with high lactate levels |
Severe diseases, mostly evolving towards neurodegeneration |
|
| Mitochondrial t-RNA: Pathogenic variants in ARS genes encoding a mitochondrial enzyme tend to cause phenotypes in tissues with a high metabolic demand. Leukoencephalopathies, myopathies, and liver disease are all common features of mitochondrial ARS disease phenotypes. Additionally, epilepsy, developmental delay, ID, ovarian failure, and sensorineural hearing loss are frequently observed in patients with mitochondrial ARS mutations56-58
|
| RARS2 (mt arginyl-tRNA synthetase) |
Pontocerebellar hypoplasia, brain stem thinning |
The same abnormalities than antenatal findings |
Perinatal. Encephalopathy with lethargy, hypotonia, epilepsy, and microcephaly |
In general these diseases evolve towards NDEG |
56, 58 |
| DARS2 (mt aspartyl-tRNA synthetase) |
Not reported |
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) |
Childhood to adulthood. Cerebellar ataxia, spasticity, dorsal column dysfunction, cognitive impairment |
|
56, 58 |
| FARS2 (mt phenylalanine-tRNA synthetase) |
Cerebral and cerebellar, brain stem and basal ganglia atrophy |
The same abnormalities than antenatal findings |
Perinatal. Epileptic encephalopathy, liver disease, and lactic acidosis |
|
56, 58 |
| MARS2 (mt methionyl -tRNA synthetase) |
Not reported |
Cerebellar atrophy and white matter alterations, thin corpus callosum |
Childhood to adulthood: autosomal recessive spastic ataxia |
|
56, 58 |
| EARS2 (mt glutamyl-tRNA synthetase) |
Not reported |
Leukoencephalopathy with thalamus and brain stem involvement and high lactate (LTBL) |
Early childhood: Global developmental delay or arrest, epilepsy, dystonia, spasticity, and high lactate |
|
56, 58 |
| TARS2 (mt threonyl-tRNA synthetase) |
Thin corpus callosum, bilateral lesion of the pallidum |
The same abnormalities than antenatal findings |
Perinatal to early childhood: psychomotor delay, hypotonia |
|
56, 58 |
| VARS2 (mt valyl-tRNA synthetase) |
Not reported |
Hyperintense lesions in the insula and frontotemporal right cortex |
Childhood. Psychomotor delay, seizures, facial dysmorphism, lactic acidosis |
|
56, 58 |
| Cytoplasmic t-RNA |
The recessive neurological phenotypes associated with cytoplasmic ARSs include hypomyelination, microcephaly, seizures, sensorineural hearing loss, and developmental delay. Some multisystem, cytoplasmic ARS-linked disorders also include liver dysfunction and lung disease. Dominant ARS-mediated disorders have, to date, a limited phenotypic range. Mutations in five ARS loci have been implicated in dominant Charcot-Marie-Tooth (CMT) disease and related neuropathic phenotypes: glycyl-(GARS), tyrosyl-(VA/ 5), alanyl-(AA/ 5), histidyl-(HARS), and tryptophanyl-tRNA synthetase (WARS). ARS-mediated CMT disease is predominantly caused by a defect in peripheral nerve axons (CMT Type 2).57
|
| VII Purines and Pyrimidines |
Diagnosis is based on P, U biomarkers (GCMS and HPLC), enzyme assays. Many enzymatic defects affecting the de novo synthesis, catabolic and salvage metabolic pathways of purines and pyrimidine involve brain development.59 A few disorders are potentially treatable like CAD deficiency that presents with an early severe epileptic encephalopathy responsive to uridine.60
|
| ABH12: a/3 hydrolase domain-containing protein 12APBD that releases arachidonic acid; ADHD; attention deficient hyperactivity disorder; APBD: adult polyglucosan body disease; ASMD: acid-sphingomyelinase deficiency; AA: amino acids; AP-5: adaptor proteins (AP 1-5) are ubiquitously expressed protein complexes that facilitate vesicle-mediated intracellular sorting and trafficking of selected transmembrane cargo proteins; AP-5 is part of a stable complex with two other proteins, spatacsin (SPG1 1) and spastizin (SPG1 5); ARCA: autosomal recessive cerebellar ataxia; ASD: autism spectrum disorder; BPAN: 3-propeller proteinassociated neurodegeneration; B4GALT1-CDG: GM2 synthetase; CAD: enzymatic complex responsible for the first three steps of the de novo pyrimidine synthesis; CER l/ll: ceramide synthetase l/ll; COG: conserved oligomeric Golgi complex (plays a major role in Golgi trafficking and positioning of glycosylation enzymes; CP: cerebral palsy; DDHD1/DDHD2: encode an A1 phospholipase; EPG-5 protein is critically involved in the late stages of the autophagy cascade such as autophagosome- lysosome fusion or proteolysis within autolysosomes; FAHN: fatty acid hydroxylase associated neurodegeneration; GBA2: Non lysosomal glucosylcerebrosidase; GCMS: gas chromatography mass spectrometry; GD2: disialoganglioside; GM1/2 monosialoganglioside; GOSR2: Golgi SNAP that indirectly regulates exocytosis; receptor GPI: Glycosylphosphatidylinositol; HSP: Hereditary spastic paraplegia; ID: intellectual disability; FA: Fatty acids; HM: hypomyelination; MKD-MA: mevalonate kinase-mevalonic aciduria; MMA Methylmalonic acid; NABP: N-ethylmaleimide-sensitive factor attachment protein beta implicated in synaptic vesicle docking; NALD: Neonatal adrenoleukodystrophy; NBIA: Neurodegeneration with brain iron accumulation; NDEG: neurodegeneration; NR: not reported; NDEV: neurodevelopmental; NPSY: neuropsychiatric; NSDHL: NAD(P) dependent steroid dehydrogenase-like; PEX: peroxin integral proteins of PZO membrane; PIGA: phosphatidylinositol glucosaminyltransferase (one of the 7 proteins require for the 1st step of the GPI synthesis); PMM2: phosphomannomutase 2; PNPLA6: phospholipase B; PLA2G6: phospholipase A2; PPRT: proline rich transmembrane protein 2 that regulates exocytosis; PZO: Peroxysome; Rabenosyn-5: multidomain protein implicated in receptor-mediated endocytosis and recycling; RCDP: rhizomelic chondrodysplasia punctata; RP: retinitis pigmentosa; SENDA: static encephalopathy of childhood with neurodegeneration in adulthood; SERAC1: protein with a lipase domain involved in the remodeling of phosphatidylglycerol, bis monoacyl glycerol phosphate and cardiolipin; SNAP 25: synaptosomal associated protein that regulates the neurotransmitter release; SNAP29: encodes for a SNARE protein involved in vesicle fusion; SRD5A3-CDG: steroid 5-alpha reductase; STXBP1:syntaxin binding protein 1 that regulates exocytosis; STX1B: syntaxin 1B that regulates exocytosis; VLCFA: very long chain fatty acids; VPS15 mutations perturb endosomal-lysosomal trafficking and autophagy; WDR45 interacts with autophagy proteins Atg2 and Atg9 to regulate autophagosome formation and elongation; WM: white matter; ZW: Zellwegger |
| (*) This variation of clinical manifestations may be common in many other disorders. Severe defects affect early developmental stages and behave as brain malformations whereas mild forms may present as “synaptopathies.” |
