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| Disease | Enzyme Defect and Genetics | Onset | Early Manifestations | Vision and Hearing | Somatic Findings | Motor Findings | Seizures | Labs | Clinical Course |
|---|---|---|---|---|---|---|---|---|---|
| White matter | |||||||||
| Globoid (Krabbe) leukodystrophy | Recessive galactocerebroside β-galactosidase deficiency. Chromosome 14q21–14q31 | Infantile form first 6 mo. Late-onset form 2–6 y. Adolescent and adult forms are rare |
Feeding difficulties Shrill cry Irritability Arching of back |
Optic atrophy Hyperacusis occasionally |
Underweight Microcephaly |
Spasticity Earlier hypotonia Decerebrate posturing |
Myoclonic Generalized | Elevated CSF protein, prolonged sural nerve conduction, enzyme deficiency in leukocytes, cultured skin fibroblasts. Demyleination and gliosis on MRI and CT. |
Rapid. Death usually by 1.5–2 y. Late-onset cases may live 5–10 y. Hematopoietic stem cell transplantation and enzyme replacement therapy is an experimental. |
| Metachromatic leukodystrophy | Recessive Arylsulfatase A (ASA) deficiency 22q13 Variant: Saposin B deficiency | Infantile form at 18–24 mo Juvenile and adult forms | Incoordination, gait disturbance, general regression. | Optic atrophy | Macrocephaly in infantile form |
Upper and lower motor neuron signs Ataxia |
Infrequent | CSF protein elevated. Urine sulfatide increased. Enzyme deficiency in leukocytes and fibroblasts. Imaging: diffuse white matter |
Moderately slow. Infantile form death by 3–8 y. Juvenile form death by 10–15 y. Hematopoietic stem cell transplantation is an experimental treatment |
| Pantothenate kinase–associated neurodegeneration (Hallervorden-Spatz syndrome) |
AR Most common chromosome 20 PANK2 gene |
Age 10 y | Rigidity, dystonia, gait disturbance, tremor | Retinal degeneration. | Extrapyramidal signs, dysarthria, hyperreflexia | Variable | Axonal degeneration (spheroids). Iron deposits in basal ganglia on MRI: eye-of-the-tiger appearance | Progressive mental/motor deterioration | |
| Pelizaeus-Merzbacher disease | X-linked recessive; rare female. Proteolipid protein (myelin) decreased. Xq22. | Birth (perinatal) to 2 y. | Eye rolling often shortly after birth. Head bobbing. Slow loss of intellect. | Slowly developing optic atrophy. Hearing normal. Nystagmus. | Head and body normal. |
Cerebellar signs Spasticity Hyperreflexia |
Usually only late |
None specific Point mutations or duplications of PLP gene account for 65%–90% of cases. |
Very slow |
| Diffuse, but primarily gray matter | |||||||||
| Poliodystrophy (Alpers disease) |
Recessive Metabolic forms |
Infancy to adolescence | Variable: regression, seizures, incoordination, hepatic failure | Cortical blindness and deafness |
Incoordination Spasticity |
Myoclonic, akinetic, and generalized |
POLG1 and mitochondrial mutations Liver steatosis and cirrhosis Muscle and liver biopsy |
Rapid with death within 1–3 y after onset Variants in older children, adults |
|
| Tay-Sachs disease and GM2 gangliosidosis variants: Sandhoff disease; juvenile; chronic-adult |
AR Hexosaminidase deficiencies caused by HEXA gene on chromosome 15q23–24.62,63. Sandhoff hexosaminidase A and B deficiency Juvenile partial hexosaminidase A. |
Tay-Sachs and Sandhoff 3–6 mo Others 2 y or later. |
Variable: shrill cry, vision loss, infantile spasms, developmental arrest. In juvenile and chronic forms: motor and mental difficulties |
Cherry-red macula Blindness Hyperacusis Juvenile form: Strabismus and late blindness |
Early hypotonia. Late decerebrate rigidity. Juvenile and chronic forms: dysarthria, ataxia, spasticity |
Infantile spasms and generalized. |
Blood smear: vacuolated lymphocytes; basophilic hypergranulation. Enzyme deficiencies in leukocytes and fibroblasts. Imaging: abnormal thalami and white matter |
Moderately rapid. Death usually by 2–5 y. In juvenile form, 5–15 y. | |
| Niemann-Pick disease and variants |
AR Sphingomyelinase deficiency in types A and C |
First 6 mo In variants onset later often non-Jewish. |
Slow development Protruding belly |
Cherry-red macula in 35%–50%. Blindness Deafness |
Early hypotonia Late spasticity Extrapyramidal signs Ataxia |
Rare and late |
Vacuolated lymphocytes X-rays: "mottled" lungs, decalcified bones Leukocyte and fibroblast enzyme deficiency |
Moderately slow Death usually by 3–5 y |
|
| Infantile Gaucher disease (glucosylceramide lipidosis) | AR | First 6 mo | Stridor or hoarse cry Feeding difficulties. | Cherry red macula. Convergent squint. Deafness | Early opisthotonos followed by decerebrate rigidity | Rare and late | Anemia X-rays: thinned cortex, trabeculation of bones. "Gaucher cells" in bone marrow. Leukocytes or fibroblasts enzyme deficiency | Rapid Experimental enzyme replacement therapy | |
| Generalized gangliosidosis and juvenile type (GM1 gangliosidoses) |
AR β-galactosidase |
Infantile: first 6 mo Late infantile: 7 mo to 3 y Juvenile onset |
Developmental arrest Protruding belly Coarse facies Juvenile form: ataxia and dysarthria |
50% "cherry-red spot." Corneal clouding Juvenile: retinitis pigmentosa |
Macrocephaly Hepatosplenomegaly Gingival hypertrophy Cardiomyopathy |
Early hypotonia Later spasticity |
Late | Vacuolated lymphocytes. X-rays: dorsolumbar kyphosis, "breaking" of vertebrae. |
Rapid within a few years Slower in juvenile type |
| Subacute necrotizing encephalomyelopathy (Leigh disease) | Variable: pyruvate carboxylase, pyruvate dehydrogenase, cytochrome enzymes, mitochondrial DNA. | Infancy to late childhood |
Feeding difficulties Feeble or absent cry Hypotonia Apnea Developmental regression Ataxia |
Optic atrophy Roving eye movements Ophthalmoplegia |
Head usually normal. Cardiac and renal tubular dysfunction |
Flaccid hypotonia Later spasticity Ataxia Myelopathy |
Rare Tonic |
Increased CSF and blood lactate and pyruvate. High-signal MRI T2 foci in thalami and basal ganglia. DNA and enzyme tests on muscle |
Usually rapid Central hypoventilation a frequent cause of death |
| Menkes disease (kinky hair disease) |
X-linked Defect in copper absorption |
Infancy |
Peculiar facies White, twisted and split hair Hypothermia |
Optic disk pallor and micro-cysts of pigment epithelium | Growth retardation | Variable: floppy to spastic |
Myoclonic infantile spasms Status epilepticus |
Cerebral angiography shows elongated arteries. Copper and ceruloplasmin low |
Moderately rapid Death usually by 3–4 y |
| Carbohydrate-deficient glycoprotein syndrome |
AR Glycoprotein abnormality |
Infancy | Failure to thrive, retardation, protein-losing enteropathy |
Strabismus Retinopathy |
Dysmorphic facies Prominent fat pads Inverted nipples |
Variable hypotonia Neuropathy |
Rare |
Normal transferrin decreased Carbohydrate-deficient transferrin increased Liver steatosis Cerebellar hypoplasia |
Cardiomyopathy Thrombosis Hepatic fibrosis |
| Abetalipoproteinemia (Bassen-Kornzweig disease) |
AR Microsomal triglyceride transfer protein (MTP) on chr 4q22–24 |
Early childhood | Diarrhea in infancy |
Retinitis pigmentosa Ophthalmoplegia |
None |
Ataxia Movement disorder |
None |
Abetalipoproteinemia: acanthocytosis, low serum vitamin E Cerebellar atrophy |
Progression arrested with vitamin E |
AR, autosomal recessive; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; ERG, electroretinogram; MRI, magnetic resonance imaging; WBC, white blood cell.
