Child With Nystagmus, Dystonia, and Developmental Failure

History and Physical

A male patient with no family history presented with psychomotor retardation from the first months of life with slow acquisition of milestones, marked axial hypotonia, and horizontal rotatory nystagmus associated with head tremor when attempting to fix gaze. He was initially diagnosed with infantile cerebral palsy and started on rehabilitation.

Diagnostic Workup

Basic laboratory tests and ophthalmological examination were normal. Metabolic studies were normal. Peripheral nerve conduction studies, electroretinography, and CSF study were also normal. Visual, auditory, and somatosensory evoked potentials were abnormal, reflecting central involvement. Head CT showed hypoattenuation of the white matter. Brain MRI was highly abnormal, with a lack of normal age-appropriate myelination, resembling the appearance of a newborn brain ( Fig. 31.1 ). On follow-up, progressive brain atrophy developed. Genetic studies were confirmatory.

A two-part axial head C T scan labeled A and B shows internal structures with multiple arrows that mark circular regions in scan A. The two-part scan is labeled A and B. Part A displays a horizontal head C T scan with one arrow that points to a rounded area near the central cavity and three additional arrows directed at circular formations on the left side. The scan reveals enlarged symmetrical ventricles and several ring-like densities in the matter. Label A appears in the lower left corner. Part B shows another axial scan labeled B, with prominent central ventricles and multiple small, rounded spots throughout the brain without arrows. — Fig. 31.1

Clinical Differential Diagnoses

Other hypomyelinating diseases with similar clinical and radiological characteristics are known as PelizaeusMerzbacher-like disease. These express autosomal recessive inheritance with other mutations such as GJC2 , AIMP1 , or HSPD . GJC2 / GJA12 (1q41-q42) encodes a protein (connexin 47) expressed in oligodendrocytes. Disease severity is less than in the X-linked form, with peripheral neuropathy and epilepsy and fewer cognitive deficits. In the classic form, brain MRI shows partial myelination of the corticospinal tracts. The connatal form is the most severe, with early onset and near-total absence of brain myelin that evolves to death in less than 2 years. Milder atypical forms associated with SPG2 mutations present with spastic paraplegia.

Other genetic leukodystrophies include Krabbe disease, Canavan disease, MLD, Alexander disease, Cockayne syndrome, trichothiodystrophy with photosensitivity or Tay syndrome, hypomyelination with atrophy of the basal ganglia and cerebellum, or hypomyelination with congenital cataracts. Clinical onset can be insidious and progression so slow that some patients are misdiagnosed as having cerebral palsy.

Other metabolic pathologies include Leigh, Leber, and Zellweger disease, Sjögren-Larson syndrome, multiple sclerosis, congenital muscular dystrophy, and rhizomelic chondrodysplasia punctata.

Imaging Differential Diagnosis

Some forms of trichothiodystrophy: MRI patterns can be very similar, although in trichothiodystrophy there are coarse calcium deposits seen by CT or MRI with susceptibility-weighted imaging (SWI).

Salla disease: Severe myelin deficiency and reduction of white matter volume. MRS can show sialic acid, which co-resonates with N-acetylaspartate at 2.02 ppm.

4H leukodystrophy: Hypomyelination along with hypogonadotropic hypogonadism and hypodontia.

Other hypomyelinating disorders: Look for additional clinical findings to narrow the diagnosis, then perform genetic testing for confirmation ( Fig. 31.2 ).