History and Physical
A 4-year-old girl with normal early development presented with a year of progressive dysarthria. Her speech was “mumbling” with decreased volume and complexity. At 3 years her articulation plateaued and began to decline: speech was 100% intelligible at 3 years, but at 4 she was only 75% intelligible. Three months prior to presentation, her diet shifted from structured meals to softer solids and frequent, small snacks. Swallowing was difficult, with dribbling of liquids. Her gait became progressively more erratic and she began falling. She preferred to crawl and required a stroller for longer distances. She regressed from one-hand dexterity to bimanual tasks. She did not improve with speech and physical therapies.
On exam, her voice was hoarse and trailed off. She drooled while speaking. Her orolingual movements were normal, without tongue atrophy. She had mild proximal weakness in the upper and lower extremities and mild rigidity in the lower extremities. Her reflexes were normal. She struggled with balance and would fall within three steps with minimal protective effort. Her gait was wide-based with irregular pacing. She could not maintain rhythms. There was no chorea, dystonia, or ataxia of the limbs or trunk, but she showed substantial ataxia with fine movements.
Diagnostic Workup
Laboratory testing, including CBC, LFTs, serum chemistry, and creatine kinase, were normal. Genetic testing demonstrated increased CAG trinucleotide repeats within the HTT gene.
Brain MRI demonstrated severe volume loss and mild T2 hyperintensity of the bilateral caudate and putamen, with ex vacuo dilation and squaring of the frontal horns. White matter was normal in volume, though there were scattered foci of signal change ( Fig. 73.1 ).
Juvenile Huntington disease. Brain MRI, (A–C) axial, sagittal, and coronal T1, illustrate striatal atrophy with increased distance between the caudate heads, (A and C) thinning of the body of the putamen, and ex vacuo enlargement of the lateral ventricles with boxlike configuration of frontal horns. (D) Axial T2 shows T2 hyperintensity in the striatum and thalamus similar to cortex. (E–H) Comparison to an age- and sex-matched healthy child shows normal size caudates ( arrowheads ) and putamina ( arrows ) with highest T2 signal in the cortex, followed by striatum and thalamus.
Clinical Differential Diagnoses
Progressive neurological symptoms—in this case, dysarthria, dysphagia, ataxia, and rigidity—raise concern for hereditary degenerative syndromes, accumulated toxins (especially heavy metals), acquired brain injury due to infection, inflammatory or autoimmune disorders, and vascular syndromes. The patient’s clinical progression was gradual and inexorable, favoring inherited neurodegeneration. There were no occupational or household routes to toxin exposure. For spinocerebellar ataxias, cerebellar and eye movement abnormalities are expected. Striatal atrophy can result from static injury, though typically coincides with other sequelae (e.g., hemosiderin deposition, leukomalacia).
Imaging Differential Diagnoses
Disorders that produce relatively selective and symmetrical injury to the striatum are unusual and include metabolic, mitochondrial, and neurodegenerative disorders.
Glutaric acidemia type 1 (GA1) typically presents before 18 months. Characteristic features include abrupt onset of encephalopathy with illness, fasting, or hypoglycemia, with severe dystonia following injury. In the acute (encephalopathic) phase, edema and restricted diffusion in the striatum are universal features. Injury may also involve the globus pallidus, substantia nigra, and/or dentate nuclei. Survivors of the encephalopathic phase uniformly have striatal atrophy, and spongiform degeneration of the white matter is common. Children with GA1 typically have macrocephaly at or shortly after birth. Reduced cortical volume, widened Sylvian fissures, and subdural hematomas are common even prior to injury ( Fig. 73.2 ).
Glutaric aciduria type I. Brain MRI, (A) axial T2 and (B) DWI show restricted diffusion (arrowheads) and cytotoxic edema ( arrows ) of the striatum and globi pallidi with enlarged and shallow sylvian fissures (asterisk).
Wilson disease (WD) presents throughout childhood, but onset before 3 years of age is unusual. Hepatic injury is near universal in childhood-onset WD; while neuropsychiatric symptoms can occur in childhood-onset WD, finding these features without hepatic injury is uncommon. T1 hyperintensity in the globus pallidus is the most common imaging finding. However, T2 hyperintensity with high frequency of striatal injury and infrequent pallidal injury can occur. Neurologic symptoms are more common in this T2-hyperintense subtype. In both T1- and T2-hyperintense forms, injury to other subcortical structures (especially thalamus and midbrain) is common.
Huntington disease (HD) results from expansions in the number of CAG repeats in the HTT gene. While typical HD onset is between 40 and 50 years, in 3–10% of patients, unusually large expansions can yield symptoms before 18 years. Developmental regression and/or dysarthria are far more common at onset than in adult HD. Rigidity and dystonia dominate the movement phenotype. One-third of children with HD develop epilepsy, a rare symptom in adult HD. Striatal atrophy typically lags symptom onset by 1–2 years. Atrophy of the thalamus, pallidum, and cortical grey and white matter is less severe than atrophy in the striatum but still significant.
Recessively inherited mutations in NUP62 cause infantile bilateral striatal necrosis (IBSN). IBSN onsets from 7 to 15 months with prominent facial chorea, progressing to limbs and trunk. Developmental regression, optic atrophy, and dystonia occur over the subsequent 1–4 years. Brain MRI is often normal early in IBSN. Progressive, symmetrical striatal atrophy with T2 hyperintensities follows later.
Biallelic mutations in VAC14 , which regulates the level of phosphatidylinositol 3,5-bisphosphate, lead to severe, generalized dystonia with striatal injury. Development is normal prior to onset of dystonia. Early descriptions of VAC14 described acute-onset dystonia at 18–37 months, but adolescent onset and slower evolution may occur. Early in the disease, susceptibility-weighted hypointensity of the substantia nigra was present in all patients, and of the globus pallidus in two of three cases with MRI. Bilateral, symmetrical striatal T2 hyperintensities were evident at disease onset in the original series, while subsequent cases had diffuse striatal T2 hypointensity.
Bilateral striatal necrosis is a common feature in ADAR1-related neuroinflammatory syndrome. ADAR1 can manifest throughout the first decade of life, though most present by 18 months. Brain MRI typically demonstrates diffuse leukodystrophy and calcifications, primarily in the caudal putamen. Diffuse volume loss is common early in the course, largely due to severe generalized leukodystrophy. ADAR1-related striatal necrosis can occur as an acute, triggered encephalopathy, or as an indolent, progressive disorder. Early developmental delay is common in ADAR1-related disorders and MDs are present at clinical onset in 60% of children.
Mutations in TUBB4A lead to hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome. Putaminal volume loss is often evident at diagnosis with subsequent progression to full atrophy. Caudate atrophy is less severe. The thalamus and pallidum are typically spared. Cerebellar (especially vermian) atrophy is common. Symptoms typically manifest at 1 to 3 years, with progressive pyramidal, extrapyramidal, cerebellar, and bulbar features. Progression to spasticity, rigidity, ataxia, dysarthria, and dysphagia are common ( Fig. 73.3 ).
