Genetic and metabolic disorders that may present with motor symptoms resembling cerebral palsy

	Type of motor disturbance	Clinical and radiographic features	Laboratory and diagnostic tests
Organic acidemias
Glutaric aciduria type 1	Dystonia	Episodes of metabolic decompensation and encephalopathy often precipitated by infection and fever Rarely presents in the newborn period Microencephalic macrocephaly Seizures (approximately 20%) Cognitive function is preserved MRI findings include frontal and temporal atrophy	Abnormal urinary organic acid analysis (elevated glutaric acid and 3-hydroxyglutaric acid)
Holocarboxylase synthetase deficiency	Hypotonia	Ketoacidosis Dermatitis Alopecia Seizures Developmental delay	Abnormal urinary organic acid analysis (elevated beta-hydroxyisovalerate, beta-methylcrotonylglycine, beta-hydroxypropionate, methylcitrate, and tiglylglycine)
Urea cycle disorders
Arginase deficiency	Spasticity	Hyperammonemia Encephalopathy Respiratory alkalosis	Elevated ammonia level Abnormal quantitative plasma amino acid analysis (elevated arginine level)
Disorders of carbohydrate metabolism
Pyruvate dehydrogenase deficiency	Spasticity Ataxia Hypotonia	Lactic acidosis Seizures Intellectual disability	Elevated lactate and pyruvate levels in blood and CSF Abnormal PDH enzymatic activity in cultured fibroblasts
Peroxisomal disorders
Zellweger syndrome	Hypotonia	Craniofacial dysmorphism Hepatomegaly Neonatal seizures Profound developmental delay MRI findings include cortical and white matter abnormalities Neurologic deterioration is rapid and infants rarely survive beyond six months of age	Elevated plasma VLCFA levels Elevated levels of phytanic acid, pristanic acid, and pipecolic acid in plasma and fibroblasts Reduced plasmalogen in erythrocytes Molecular genetic testing for variants in the PEX1 or PEX6 genes may also be helpful
Adrenoleukodystrophy and adrenomyeloneuropathy	Spasticity	Clinical features vary by specific type, and may include: Cognitive and behavioral abnormalities Adrenal insufficiency Hyperpigmented skin Gonadal dysfunction Neurologic deterioration progresses at a variable rate	Elevated plasma VLCFA levels Molecular genetic testing for variants in the ABCD1 gene may be helpful in cases with borderline VLCFA levels or atypical features, or in females
Infantile Refsum disease	Hypotonia Ataxia	Abnormalities of the optic nerve and disc Retinitis pigmentosa Sensorineural hearing loss Hepatomegaly and cirrhosis Neurologic deterioration is slower than in Zellweger syndrome or ALD	Elevated plasma VLCFA levels, though less pronounced than in Zellweger syndrome and ALD
Lipid storage disorders
Niemann-Pick disease type C	Ataxia Dystonia	Progressive neurodegeneration Hepatosplenomegaly Systemic involvement of liver, spleen, or lung precedes neurologic symptoms MRI shows cerebral and cerebellar atrophy and thinning of the corpus callosum	Abnormal liver function tests Fibroblast cell culture with filipin staining
Mitochondrial disorders
Leigh syndrome	Ataxia Dystonia	Progressive psychomotor regression Seizures External ophthalmoplegia Lactic acidosis Vomiting MRI shows abnormal white matter signal in the putamen, basal ganglia, and brainstem on T2 images	Increased lactate levels in blood and CSF Genetic testing for specific variants (>20 have been described)
Others
Angelman syndrome	Ataxia	Profound intellectual disability Postnatal microcephaly Typical abnormal behaviors (paroxysmal laughter, easily excitable)	Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A genetic variants
Ataxia-telangiectasia	Ataxia	Progressive cerebellar ataxia Abnormal eye movements Oculocutaneous telangiectasias Immune deficiency Increased risk of malignancy	Elevated serum alpha-fetoprotein level Low IgA and IgG levels Lymphopenia Genetic testing for variants in the ATM gene
Congenital myotonic dystrophy	Hypotonia	Facial diplegia Arthrogryposis Poor feeding Intellectual disability	Genetic testing for DMPK variants Electromyography showing myotonic discharges Electrocardiography may show cardiac conduction abnormalities
Dopa-responsive dystonia	Focal dystonia Spastic diplegia	Onset in early childhood Symptoms worsen with fatigue and exercise	Positive response to a trial of levodopa
Hereditary spastic paraplegia	Spastic paraplegia	Variable depending on specific genetic variant	>50 genetic variants have been identified Genetic testing is available for many
Lesch-Nyhan syndrome	Choreoathetosis Dystonia Spasticity	Self-mutilating behavior Urinary stones due to hyperuricemia	Elevated uric acid level Abnormal enzymatic activity of HPRT in cultured fibroblasts Genetic testing for HPRT variants
Metachromatic leukodystrophy	Hypotonia Ataxia	Regression of motor skills Seizures Optic atrophy Reduced or absent deep tendon reflexes Intellectual disability	Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts
Miller-Dieker lissencephaly	Hypotonia or spasticity	Lissencephaly Microcephaly Dysmorphic features Seizures Failure to thrive	Cytogenetic testing for 17p13.3 microdeletion
Pelizaeus-Merzbacher	Spasticity Ataxia Athetosis	Nystagmus Cognitive impairment Onset in infancy Slowly progressive Language development may be normal MRI shows white matter abnormalities	Genetic testing for variants in PLP1 gene
Pontocerebellar hypoplasias	Hypotonia Dyskinesias	Clinical features vary by specific type, and may include: Progressive muscle atrophy Microcephaly Developmental delay MRI shows small cerebellum and brainstem including the pons	Genetic testing for PCH gene variants (variants in >10 genes have been described)
Rett syndrome	Dystonia Spasticity	Occurs almost exclusively in females Normal development during first six months followed by regression and loss of milestones Loss of speech capability Stereotypic hand movements Seizures Autistic features	Clinical diagnosis Genetic testing for MECP2 variants may be helpful
Aicardi-Goutieres	Spasticity Dystonia	Infantile spasms Abnormal eye movements Truncal hypotonia Intellectual disability MRI shows agenesis of the corpus callosum and calcifications of the basal ganglia and periventricular areas	Lymphocytic pleocytosis in CSF Genetic testing for pathologic variants in TREX1

This list is not exhaustive. Refer to UpToDate topics on cerebral palsy for further details.

VLCFA: very long chain fatty acids; PDH: pyruvate dehydrogenase; HPRT: hypoxanthine phosphoribosyltransferase; CSF: cerebrospinal fluid; PCH: pontocerebellar hypoplasias; MRI: magnetic resonance imaging; Ig: immunoglobulin; ATM: ataxia-telangiectasia mutated; ALD: adrenoleukodystrophy.

Graphic 102942 Version 3.0

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Genetic and metabolic disorders that may present with motor symptoms resembling cerebral palsy