Mucopolysaccharidoses are caused by defective lysosomal hydrolases resulting in the accumulation of mucopolysaccharides within lysosomes (see Chapter 56). The clinical manifestations include coarse facies, short stature, kyphoscoliosis, hepatosplenomegaly, cardiovascular abnormalities, and corneal clouding. Neurologic involvement is seen in mucopolysaccharidosis types I (Hurler syndrome), II (Hunter syndrome),III (Sanfilippo syndrome), and VII (Sly syndrome). Children with Hurler syndrome, the most severe of these illnesses, appear normal during the first 6 months of life, then develop the characteristic skeletal and neurologic features. Intellectual disability, spasticity, deafness, and optic atrophy are progressive. Hydrocephalus frequently occurs because of obstruction to cerebrospinal fluid (CSF) flow by thickened leptomeninges.
Mitochondrial diseases represent a clinically heterogeneous group of disorders that fundamentally share a disturbance in oxidative phosphorylation (adenosine triphosphate synthesis) (Chapter 57). Abrupt symptoms are often manifest concurrent with periods of physiologic stress such as febrile illness or fasting. Specific genetic diagnoses are often difficult to identify because clinical features are pleotropic within individual defects and overlap between different defects, and because analysis of mitochondrial protein function is technically demanding. Specific syndromes include MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes); MERRF (myoclonus, epilepsy, and ragged red fibers) which can also manifest as combinations of dementia, sensorineural hearing loss, optic nerve atrophy, peripheral neuropathy, and occasionally cardiomyopathy with Wolff-Parkinson-White syndrome; and NARP (neuropathy, ataxia, and retinitis pigmentosa).
Rett syndrome is a neurodevelopmental disorder that classically affects girls. Typically, development appears normal during the first 6 to 18 months of life, followed by regression, loss of purposeful hand movements, loss of verbal communication skills, gait apraxia, and stereotypic repetitive hand movements that resemble washing, wringing, or clapping of the hands. Girls also develop acquired microcephaly. Episodic apnea and/or hyperpnea, peripheral vasomotor disturbances, growth retardation, abnormal muscle tone, and prolonged QTc interval often occur. The regression plateaus and stabilizes, but seizures, spasticity, and kyphoscoliosis develop. The etiology is a mutation on an X chromosome gene coding for methyl-CpG-binding protein 2 transcription factor. Boys with MECP2 mutations usually do not survive to delivery, but can present with severe neonatal encephalopathy, seizures, microcephaly, abnormal tone, and respiratory insufficiency.
Degenerative Diseases with Focal Manifestations
Some neurodegenerative disorders have predilections to target specific regions or systems within the neuraxis, producing symptoms referable to the affected region.
Wilson disease is a treatable degenerative condition thatexhibits signs of cerebellar and basal ganglia dysfunction. It is anautosomal recessive inborn error of copper metabolism. Serumceruloplasmin levels are low. Abnormal copper deposition isfound in the liver, producing cirrhosis; in the peripheral cornea, producing a characteristic green-brown (Kayser-Fleischer)ring; and in the CNS, producing neuronal degeneration andprotoplasmic astrocytosis. Neurologic symptoms characteristically begin in the early teenage years with dysarthria, dysphasia,drooling, fixed smile, tremor, dystonia, and emotional lability.MRI shows abnormalities of the basal ganglia. Treatment is witha copper-chelating agent, such as oral penicillamine.