Neuroimaging

Brain MRI is a first-line investigation that can provide helpful diagnostic clues. For patients with progressive spasticity, involvement of the pyramidal tract is likely, and a disease-specific pattern of involvement should be sought. MRI patterns that may be suggestive of a specific disorder can then guide the provider to targeted biochemical or genetic confirmatory testing (Table 10.2). White matter involvement that is parieto-occipital may be suggestive of X-ALD, while a more frontal pattern may be more suggestive of metachromatic leukodystrophy (MLD). T2 lesions of cerebellar and dentate nuclei may be a feature of Krabbe disease or cerebrotendinous xanthomatosis. Variable basal ganglia involvement may point to other lysosomal storage disorders, but basal ganglia involvement (or necrosis in severe cases) can also be found in mitochondrial disorders and organic acidurias (Table 10.2). Additional imaging techniques, such as MRS can also be helpful tools. A lactate peak may be present on MRS in mitochondrial encephalopathies, and an elevated N-acetyl-aspartate (NAA) peak suggests a possible diagnosis of Canavan disease.

Urea Cycle Defects

Arginase deficiency, also known as argininemia, is an autosomal-recessive urea cycle disorder caused by mutations in ARG1. Symptoms typically begin in late infancy, following a period of normal motor development in the first year, but the insidious onset and gradual progression of symptoms may lead to an initial misdiagnosis of spastic diplegic cerebral palsy. The progressive nature of both the spasticity and cognitive dysfunction eventually becomes evident if the disease is not diagnosed and treated early. Common accompanying neurological features are intellectual disability and seizures. Some patients experience intermittent episodes of irritability, vomiting, and lethargy associated with hyperammonemia, but unlike other urea cycle defects, episodes of recurrent hyperammonemic encephalopathy may be absent in patients with arginase deficiency. The diagnosis is suggested by the detection of elevated plasma arginine. In many countries, this is performed as part of newborn screening. In an older child, it can be detected on plasma amino acid analysis. The diagnosis is now typically confirmed with molecular genetic analysis for sequence or copy number variants in ARG1. Red blood cell arginase enzyme analysis is an alternative confirmatory test if results of molecular analysis are inconclusive.

HHH syndrome is a rare urea cycle disorder caused by mutations in the SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1 [2]. In infancy and early childhood, the disorder tends to present acutely with encephalopathy and seizures, or with fulminant liver failure and coagulopathy, with or without overt hyperammonemia. Patients with later-onset disease may present more insidiously, with slowly progressive spasticity, intellectual disability, ataxia, and myoclonic seizures. Disease severity is quite variable, and does not correlate reliably with genotype, recorded ammonia levels, or age of onset. The long-term treatment consists of a low-protein diet supplemented with citrulline or arginine. In addition, some patients require sodium benzoate and/or sodium phenylbutyrate to maintain blood ammonia in a safe range.

Dopa-Responsive Dystonia

Dopa-responsive dystonia is a disorder of monoamine neurotransmitter synthesis, most commonly caused by deficiency of GTP cyclohydrolase type 1. The classic presentation is of childhood-onset progressive limb dystonia with diurnal variation. The finding of hyperreflexia is not uncommon, and this, in combination with dystonic leg posturing, may mimic spastic paraparesis. Worsening of symptoms in the afternoon and evening is an important diagnostic clue, if present. A trial of levodopa typically leads to a rapid and dramatic improvement in symptoms, and should be considered in any child who presents with lower limb spasticity or dystonia in the context of normal brain imaging.

GLUT1 Deficiency Syndrome

Spasticity is one of the core motor features in glucose transporter type 1 (GLUT1) deficiency syndrome, a disorder in which glucose transport across the blood–brain barrier is impaired due to a deficiency of GLUT1, usually resulting from a heterozygous loss-of-function mutation in SLC2A1. In the classic, infantile-onset form of the disorder, spasticity is typically accompanied by ataxia and dystonia, and patients have a spastic–ataxic gait pattern. The earliest symptoms in infants are usually either seizures, or characteristic episodes of repetitive, multidirectional shifts of gaze that manifest as eye–head movements. Ataxia often fluctuates, worsening in the context of exercise, illness or fasting. Some patients develop paroxysmal exercise-induced dyskinesia during childhood. Intellectual disability in this disorder ranges from mild to severe. Cerebrospinal fluid (CSF) analysis reveals low CSF glucose in the setting of a normal blood glucose concentration, and CSF lactate is low or low–normal. Treatment with the ketogenic diet leads to a dramatic improvement in the paroxysmal and fluctuating symptoms (including ataxia, seizures, and paroxysmal dyskinesia), and may improve the long-term developmental outcome.

Homocysteine Remethylation Defects

The homocysteine remethylation disorders are rare autosomal-recessive conditions that have the common feature of deficient activity of methionine synthase, the enzyme responsible for the remethylation of homocysteine to form methionine. This may result from an abnormality of methionine synthase itself, deficiency of the related enzyme (methionine synthase reductase) or cofactor (methylcobalamin), or insufficient supply of the substrate (methionine tetrahydrofolate, MTHF). As a result, there is accumulation of homocysteine, and in the case of some cobalamin transport defects, combined accumulation of homocysteine and methylmalonic acid [3]. The two most common remethylation disorders are MTHF reductase deficiency and cobalamin C deficiency. Remethylation defects usually present in early childhood with seizures, cognitive impairment, and acquired microcephaly. Gait abnormalities due to spasticity and peripheral neuropathy become increasingly evident with age [3]. Older patients may develop dementia and subacute combined degeneration of the spinal cord. Presentation with encephalopathy, accompanied by hypotonia and feeding difficulties, is typical in neonates and young infants, but acute encephalopathy may occur at any age. There is considerable clinical variability in presentation, but the combination of the central and peripheral nervous system and bone marrow involvement may alert the clinician to the diagnosis. The finding of elevated plasma total homocysteine on biochemical screening should be followed by analysis of plasma methionine, blood acylcarnitine profile, serum vitamin B12 and folate, and urinary (or plasma) methylmalonic acid prior to starting treatment. Treatment with betaine, in combination with parenteral hydroxycobalamin for the cobalamin-related disorders, improves outcome and prevents long-term neurological complications.

Biotinidase Deficiency

Biotinidase deficiency is a treatable autosomal-recessive disorder that classically presents in infancy with seizures, hypotonia, and developmental delay, usually accompanied by seborrheic skin rash and alopecia. If untreated, other neurological features develop in time, including ataxia, hearing loss, and vision loss [4]. Some children develop progressive spastic paraparesis associated with myelopathy [5]. Patients have also been reported who were asymptomatic in childhood and developed acute vision loss with optic neuropathy and progressive spastic paraparesis in adolescence [6]. Critically, biotin supplementation can reverse neurological deficits and prevents disease progression.

Cerebral Folate Deficiency

Cerebral folate deficiency is associated with low levels of 5-methyltetrahydrofolate in the CSF with normal plasma folate levels. The most common cause of cerebral folate deficiency is blocking autoantibodies to the folate receptor that inhibit methyltetrahydrofolate transport across the choroid plexus [7]. Bi-allelic mutations in FOLR-1, encoding the folate receptor, are comparatively rare. Symptom onset typically occurs at 4–6 months of age with hypotonia, irritability, developmental delay, and acquired microcephaly. A mixed motor syndrome, variably characterized by hypotonia, ataxia, spasticity, dystonia, and chorea, develops during childhood. Patients often have epilepsy and autistic behavioral features. If untreated, visual and hearing loss may develop. Treatment with folinic acid may result in significant clinical improvement.

Cerebrotendinous Xanthomatosis

Cerebrotendinous xanthomatosis is an autosomal-recessive lipid storage disease caused by mutations in the CYP27A1 gene, which encodes sterol 27-hydroxylase, an enzyme involved in bile acid synthesis. The resulting bile acid deficiency leads to increased liver production of cholesterol metabolites, including cholestanol, and their accumulation in multiple body tissues. The disease typically presents during childhood with bilateral cataracts and intractable diarrhea, followed in adolescence or early adulthood by the development of characteristic Achilles tendon xanthomas. Progressive neurological symptoms typically become evident in early adulthood, with ataxia, spasticity, and cognitive decline. Seizures, psychiatric symptoms, and peripheral neuropathy are less common disease features [8, 9]. A rare spinal form of the disease is characterized by slowly progressive myelopathy with pyramidal-tract and dorsal-column signs [10]. Treatment with chenodeoxycholic acid normalizes bile acid synthesis and plasma and CSF cholestenol concentration, and can prevent progression of the neurological manifestations.

Phenylketonuria (PKU)

PKU is an autosomal-recessive disorder caused by deficiency of phenylalanine hydroxylase, leading to hyperphenylalaninemia. Patients are now typically diagnosed by newborn screening. The early-onset classic form is characterized by intellectual disability, behavior problems, microcephaly, and seizures. The goal of treatment is to normalize blood concentrations of phenylalanine which is achieved with dietary restriction of phenylalanine, together with sapropterin (tetrahydrobiopterin) cofactor supplementation in patients who are responsive. Treatment effectively prevents the development of spastic quadriparesis and intellectual disability, associated with signs of progressive white matter disease on MRI, which would develop during the natural course of the untreated disease. Development of spastic quadriparesis upon cessation of a phenylalanine-restricted diet in young adulthood, and subsequent improvement with reintroduction of dietary therapy, has been reported [11].

Molybdenum Cofactor Deficiency

Molybdenum cofactor deficiency is a rare autosomal-recessive disorder that classically presents with neonatal onset of intractable seizures and feeding difficulties, followed by progressive microcephaly, intellectual disability, and spastic quadriparesis. Patients also have dysmorphic facial features, and may develop lens subluxation during childhood. The disease is caused by mutations in either MOCS1, MOCS2, or GPHN. Once the disease is suspected based on clinical and biochemical features, molecular analysis should be performed to identify the subtype: in patients with type A (MOCS1, approximately two-thirds of cases) early treatment with cyclic pyranopterin monophosphate dramatically improves the neurological outcome [12].

Lysosomal Storage Disorders

Krabbe disease, or globoid cell leukodystrophy, inherited in an autosomal-recessive manner, is due to mutations in the GALC gene and is associated with very low enzymatic activity of galactocerebrosidase. The majority of patients have infantile-onset symptoms. Typically, after a brief period of normal development, infants develop inconsolable irritability, limb hypertonia, and truncal hypotonia [13]. Symptoms are progressive, with poor feeding, blindness, seizures, and loss of milestones, ultimately leading to death within the first 2 years [14]. MRI shows periventricular T2 hyperintensity and dentate/deep cerebellar T2 hyperintensity, although the dentate/cerebellar findings may not be present in later-onset cases [15]. A demyelinating peripheral neuropathy on nerve conduction studies is also characteristic [16], with diminished or absent reflexes on examination. Early stem-cell transplantation has been shown to provide improved function, but still with variable motor and cognitive involvement, and some patients continue to have moderate to severe spasticity [17].

Metachromatic leukodystrophy (MLD), or arylsulfatase A deficiency, is caused by mutations in the ARSA gene and leads to accumulation of sulfatides in the nervous system causing damage to the myelin sheath. MLD is commonly divided into three categories based on age of presentation: late-infantile MLD presents at 30 months or younger, juvenile MLD presents between 30 months and 16 years, and adult MLD presents after age 16 years. Earlier presentation usually portends a more rapid neurological decline. Late-infantile MLD patients often present with motor decline, spasticity, and seizures, while later-onset MLD (juvenile and adult) presents with both motor and cognitive decline, such as worsening school performance or psychosis in adults [18]. Demyelinating neuropathy is a common feature in all subtypes of MLD, with notable multifocal slowing of nerve conduction velocities [19]. MRI changes start with frontal and periventricular white matter T2 hyperintensity, and progress to include subcortical white matter with a characteristic tigroid appearance (due to sparing of perivascular white matter) [20]. Systemic involvement may include gallbladder polyposis and increased risk of gallbladder carcinoma due to sulfatide accumulation [21]. Treatment with stem-cell transplantation in the presymptomatic or very early symptomatic stage of disease may halt disease progression [22].

In multiple sulfatase deficiency, caused by autosomal-recessive mutations in the SUMF1 gene, there is faulty post-translational activation of all sulfatases and thus a clinical presentation that combines MLD with other sulfatase deficiencies including multiple mucopolysaccharidoses, X-linked ichthyosis, and chondrodysplasia punctata with coarse features, organomegaly, dermatological abnormalities, and dysostosis multiplex [23]. Neurologically, motor deterioration, peripheral neuropathy, and seizures may all be features; imaging may be similar to MLD but hydrocephalus is also a reported feature [23].

GM1 gangliosidosis, associated with mutations in the GLB1 gene, results in the accumulation of GM1 ganglioside in tissues including the central nervous system. GM1 gangliosidosis has a range of phenotypic presentations from early infantile to adult onset. The infantile presentation (type 1) is the most severe, and is associated with motor delay, hypotonia that progresses to spasticity, and occasionally seizures. Accompanying systemic features include a retinal cherry red spot, skeletal dysplasia, hepatosplenomegaly, and cardiomyopathy [24]. Type 2 GM1 gangliosidosis, or the late-infantile/juvenile type, has a later age of onset and a slower progression; skeletal dysplasia may be present but juvenile onset disease is less likely to have organomegaly [24]. On MRI, hypomyelination with T2 hyperintensity of the basal ganglia can be found in infantile-onset GM1 but later-onset disease may have normal imaging [25]. Extrapyramidal symptoms such as dystonia and parkinsonism can be present in an adult onset form of the disease, but are not typically features of earlier onset GM1 [26]. In a very limited case series of patients with juvenile or adult-onset GM1, there was a slowing of progression or an improvement in some motor symptoms with substrate reduction therapy [27]

GM2 gangliosidosis refers to several different disorders that result in the abnormal accumulation of GM2 gangliosides: hexosaminidase A deficiency (Tay–Sachs), Sandhoff disease, or AB variant GM2 gangliosidosis. Phenotypically these disorders all appear relatively similarly, but can be distinguished biochemically; there is absent HEX A enzymatic activity but increased HEX B activity in individuals with Tay Sachs, absent HEX A and HEX B activity in Sandhoff disease, and normal HEX A and HEX B activity in the AB variant, as this variant is due to an abnormality in the GM2 activator. Clinically, these may be indistinguishable. GM2 gangliosidosis is often divided into categories based on severity and age at presentation: infantile/acute, juvenile/subacute, and adult/chronic forms. Infantile acute-onset disease presents in infancy and is characterized by developmental regression, axial hypotonia with limb spasticity, seizures, and blindness with a characteristic cherry-red spot on the fovea that can be seen on funduscopic examination [28]. Hypomyelination with T2 hyperintensity of the basal ganglia on MRI is not distinguishable from findings on MRI for infantile GM1 gangliosidosis, as above [25]. Juvenile GM2 gangliosidosis often starts with gait and coordination disturbance but may then be followed by spasticity, seizures, and cognitive decline [29]. Adult-onset hexosaminidase deficiency presents with cognitive decline that can include psychiatric features or psychosis, a combination of spasticity and lower motor neuron features such as fasciculations that can resemble amyotrophic lateral sclerosis, ataxia, and dystonia/parkinsonism [30].

Fucosidosis is a storage disorder caused be deficiency of alpha-L-fucosidase. There is a clinical continuum of severity, but a more severe phenotype (type 1) that rapidly progresses to death within the first decade and milder phenotype (type 2) with a more prolonged survival have been described, although different types can coexist within the same family [31]. Patients present with neurological features including motor regression, spasticity, and seizures, and systemic features including coarse facial features, organomegaly, skin changes such as angiokeratoma corporis diffusum and telangiectasias, and dysostosis multiplex [31]. Brain MRI shows characteristic basal ganglia T2 hypointensity in addition to hypomyelination [25].