Hypotonia and weakness may signify a variety of systemic, neurologic, and neuromuscular disorders (Table 120-1). Evaluation of hypotonia and weakness can be challenging, as the list of possible diagnoses is extensive and includes many rare conditions. A logical first step in the evaluation is to localize the lesion to the central nervous system (CNS) or the peripheral nervous system (PNS), which frequently can be accomplished by detailed birth and medical history, along with thorough general and neurological examination. Localization will help to narrow the list of differential diagnoses and guide subsequent investigations to reach a specific diagnosis. It is important that pediatric hospitalists are knowledgeable of the general approach to this group of patients, and have a basic understanding of the diagnostic possibilities and their clinical presentations, pathophysiology, diagnosis, and associated morbid conditions as well as management.

CNS (or upper motor neuron [UMN]) diseases affect the neural pathway at any point from their origin in the cortex to above the anterior horn cells of the spinal cord or motor nuclei of the cranial nerves. PNS (or lower motor neuron [LMN]) diseases are further localized to the anterior horn cells, spinal roots, brachial or lumbosacral plexus, peripheral nerves, neuromuscular junctions, or muscle fibers. Overlap occurs in processes that affect both central and peripheral myelin, such as metachromatic leukodystrophy, or those that involve multiple tissues, as in mitochondrial disease or myotonic dystrophy.

HISTORY

An infant or a child presenting with weakness or hypotonia requires a thorough history and a comprehensive physical and neurological examination. Initial symptoms vary by age at presentation. During neonatal period and infancy, patients frequently present with poor tone (i.e. “floppy”) or with delay in achieving developmental milestones. In older children, the most common complaints relating to weakness include an unusual gait, frequent falls, inability to run or climb stairs, inability to keep up with peers, inability to lift heavy objects, and clumsiness with fine motor function such as writing and manipulating fine objects. It is particularly important to try to clarify by careful questioning and examination whether these signs reflect problems of strength or coordination.

Distinctive features in birth and medical history, family history, and physical examination frequently allow the localization of lesion to CNS or PNS, or both. Infants with hypoxic ischemic encephalopathy are expected to have a history of prenatal or perinatal complications, anoxia/hypoxia, low cord pH, and low Apgar scores. A history of infection during pregnancy, especially during the first trimester, raises a concern for in-utero infection or exposure to systemic inflammation, potentially exacerbating hypoxic injury. Decreased fetal movements, polyhydramnios, or breech presentation may be reported in infants with neuromuscular disorders. A maternal history of multiple late spontaneous abortions suggests an inherited condition. A history of seizures and cognitive impairment or syndromic features, such as facial dysmorphisms or other congenital malformations, offers support for a central origin.

Information about the time course of symptom development (static or progressive) is an important element in sorting the diagnostic possibilities. When hypotonia or weakness occurs acutely in an otherwise healthy infant or child, they are most commonly the result of severe infection, fluid or electrolyte derangements, toxic ingestion, immune-mediated process, trauma, or mass lesion(s). If present at birth, they may be the result of injury to the nervous system or due to brain malformation or genetic diseases. Progressive hypotonia and weakness may herald the onset of a number of neurodegenerative diseases.

PHYSICAL EXAMINATION

Muscle tone and power should be evaluated when the child is awake and comfortable and should be delayed if possible in sick children or children with malnutrition. The evaluation can also be compromised by medications. It is important to distinguish hypotonia (reduced resistance to passive range of motion) from muscle weakness (reduced maximum power generated). A weak infant is often hypotonic, but hypotonic infants are not necessarily weak.

Tone in an infant or a child is assessed by passive and active maneuvers. The overall resting posture of a hypotonic infant shows decreased flexion in the arms, with legs flexed at the hips and externally rotated (“frog leg” posture). Passive maneuvers require only gravity to stretch the muscles. A hypotonic infant supported beneath the axillae (vertical suspension) will slip through the hands of the examiner unless lateral pressure is exerted. An inverted “U” curvature of the spine is observed while the infant is held prone in one hand of the examiner (Landau maneuver). Poor head control and head lag are seen on “pull to sit.” Active maneuvers are those in which the examiner actively stretches the muscle, such as those used to assess immaturity on the Dubowitz scale (heel-to-ear or scarf sign). Ligament laxity, which may occur in connective tissue disorders or in marked hyperextensibility as a normal variant, may be mistaken for hypotonia.

In infants younger than 18 months, both upper and LMN lesions may present initially as hypotonia as a result of incomplete myelination of the corticospinal tracts. Many patients with central hypotonia may evolve to have appendicular hypertonia while retaining axial hypotonia as they get older. For example, an infant with kernicterus due to hyperbilirubinemia is initially hypotonic but becomes hypertonic over time. The presence of upper or LMN signs (Table 120-2) will help to localize the lesion. Clonus, hyperreflexia, and extensor responses signify UMN dysfunction. Retained primitive reflexes such as the Moro or asymmetric tonic neck reflex may indicate CNS immaturity.

The central component of motor examination in a weak patient is strength testing. Strength may be difficult to assess in an infant. Hypotonic infants frequently have paucity of spontaneous movement. With stimulation, hypotonic infants without muscle weakness usually demonstrate antigravity limb movements, whereas hypotonic weak infants frequently do not. Other signs of weakness can be inferred by a weak cry, paradoxical breathing pattern (“belly breathing”), swallowing difficulty manifesting as poor suck, slow feeding, oropharyngeal pooling of secretion or food, or choking. Frequently, formal muscle strength testing can’t be performed in younger children due to lack of cooperation or lack of understanding of the testing; thus functional testing is necessary. Functional testing includes watching the child walk, run, stand up from a supine position, and climb stairs. A spastic hemiparetic gait is characterized by circumduction of the affected leg, and frequently accompanied by arm adduction (held close to the body) and elbow flexion with hand pronation, often with cortical thumb (thumb held under the fingers or “palmed”) on the same side. With mild hemiparesis, loss of normal arm swing and slight circumduction of the leg may be the only abnormalities. Scissoring gait, frequently accompanied by crouching at the knees and toe walking, is seen in spastic diplegia due to tightness of hip adductors, hamstrings and calf muscles. With proximal weakness, the pelvis is not stable and waddles from side to side as the child walks (Trendelenburg sign). Running is particularly difficulty or impossible and accentuates the waddling. The Gowers sign is when a child rises from a supine position on the floor by turning to prone, using hands to first push off the floor and then to “climb” up his/her legs. Difficulty with ascending stairs suggests hip extensor weakness and difficulty with descending stairs is seen in quadriceps (flexor) weakness. Push-ups are a good test of muscle strength in arms. A child with shoulder girdle or upper arm muscle weakness has difficulty with “wheelbarrow walk.” With distal leg weakness, the child has difficulty with heel-walk due to weakness of anterior compartment muscles (shin) of the legs. Difficulty with toe-walk suggests weakness of gastrocnemius muscles (calf). Children with foot drop tend to raise their knee high in air so the toes can clear the ground, then the weak leg comes down with a slapping motion (high steppage gait) (Table 120-3). Muscle strength in older and cooperative children can be graded with the Medical Research Council (MRC) grading scale (Table 120-4).

Assessment of the pattern of sensory/motor change should help to localize the lesion. Weakness with UMN signs may present with hemiparesis, quadriparesis, or paraparesis. Oculomotor dysfunction and cranial nerve dysfunction in this setting indicate midbrain and brainstem involvement. Hemiparesis with facial involvement localizes the lesion to the brain contralateral to the paretic side. Quadriparesis can be the result of bilateral brain disease, brainstem involvement, or a cervical spinal cord process. Paraparesis with sparing of the arms raises a concern for a spinal cord disease at the thoracic or lumbosacral region, although periventricular brain lesion (as in periventricular leukomalacia) can present with paraparesis. Bilateral weakness accompanied by a sensory level and incontinence indicates spinal cord disease and is a neurological emergency. Focal weakness with LMN signs indicates lesion in the spinal roots, plexus, or a mononeuropathy; there is usually suggestive history of a trauma or a compressive injury in the affected side. In LMN diseases, patients with anterior horn cell diseases, neuromuscular junction defect, or myopathies typically have proximal > distal weakness, and patients with a neuropathy often have distal > proximal weakness.

Head circumference and head shape as well as other dysmorphic features may help to identify a cause for the differences in tone and/or strength. Tongue fasciculations are associated with denervation in bulbar motor neuron disorders and are characteristic of spinal muscular atrophy (SMA) and syringobulbia. Retinal pigmentary degeneration or optic atrophy is frequently seen in certain metabolic disorders. Cherry-red spot of the macula may be present in some lysosomal disorders. Organomegaly is seen in infectious process or in storage diseases such as glycogen storage disease, lysosomal disorders, or mucopolysaccharidosis.

Neonates and infants with CNS diseases frequently present with congenital hypotonia. Older children may present with motor delay, psychomotor delay or regression, or acute/subacute onset of weakness. The diagnostic considerations vary and depend on the age of onset and the time course of symptom development.

CEREBRAL (CENTRAL) HYPOTONIA

Almost every cerebral disorder in newborns and infants presents with hypotonia. A variety of perinatal events can damage UMN structures and result in congenital hypotonia, including infections with the TORCH organisms (toxoplasmosis, other [congenital syphilis and viruses], rubella, cytomegalovirus, and herpes simplex virus), toxic exposure, injury resulting from trauma, intracranial bleeding, and hypoxic ischemic injury. Other causes of central hypotonia include brain dysgenesis, chromosomal/genetic syndromes (such as trisomy 21, Prader-Willi syndrome [PWS], Zellweger syndrome, and neonatal adrenoleukodystrophy), and metabolic disorders. Hypothyroidism may present with hypotonia and failure to thrive. In addition, transient neonatal hypotonia can be seen in the setting of systemic illness. Electrolyte disturbance, especially hypermagnesemia due to magnesium sulfate infusion to the mother with eclampsia or to prevent preterm delivery, frequently result in neonatal hypotonia, hyporeflexia, and respiratory depression.

PRADER-WILLI SYNDROME

PWS is a complex genetic condition.¹ Approximately 70% of children with PWS have an interstitial deletion of the proximal long arm of chromosome 15 (q11-3). Most patients without the deletion of chromosome 15 (q11-3) have maternal uniparental disomy (i.e. both copies of chromosome 15 are inherited from the mother instead of one copy from each parent).

Clinical Features

About 10% of affected individuals are born with congenital hip dislocation and 6% with congenital clubfoot. Dysmorphic features include narrow forehead, almond-shaped eyes, triangular face, enamel hypoplasia, short stature, and small hands and feet; these may not be evident during the neonatal period but become more obvious in later infancy. Infants with this condition have profound hypotonia, feeding difficulties, poor growth, and delayed development. The profound hypotonia can be easily mistaken for a presentation of SMA but is differentiated by the presence of deep tendon reflexes (DTR). The profound hypotonia improves with age, though affected children often remain hypotonic. Beginning in early childhood, affected individuals develop an insatiable appetite, which leads to chronic overeating and morbid obesity. Patients typically have mild to moderate intellectual impairment and learning disabilities. Behavioral problems are common. Cryptorchidism is present in 84% and hypogenitalism in 100% of affected individuals. Puberty is delayed or incomplete, and most affected individuals are infertile.

Diagnosis

Deletion analysis by FISH or whole genome microarray detects about 70% of individuals with PWS. DNA methylation testing detects abnormal parent-specific imprinting within the Prader-Willi critical region on chromosome 15, and confirms the diagnosis of PWS in more than 99% of affected individuals.

Management

No specific treatment is available. In infancy, enteral tube feeding may be needed to assure adequate nutrition. In childhood, strict supervision of daily food intake is essential to limit weight gain. Sex hormone replacement at puberty may help to produce adequate secondary sexual characteristics. Behavioral management might be challenging.

CHRONIC STATIC (NON-PROGRESSIVE) ENCEPHALOPATHY AND CEREBRAL PALSY

Chronic static encephalopathy (CSE) of infancy and childhood is a term used by neurologists in recent years to refer to chronic, permanent, and non-progressive brain disorders, with resultant cognitive and motor impairment. This terminology does not imply specific etiology. The symptoms and effect on development depend on the part(s) of the brain are involved and the severity of the injury. CSE can be due to acquired conditions such as hypoxic ischemic brain injury, trauma, infection, or in-utero toxic exposure as in fetal alcohol syndrome, specific congenital mental retardation syndromes, or congenital brain malformation.

Cerebral palsy (CP) is a broad term used to describe a heterogeneous group of disorders affecting motor control and posture due to damage to the immature and developing brain, especially the corticospinal tract or the cerebral white matter. CP is typically present early in life and is not caused by a degenerative disorder. CP is the most common childhood physical disability, with an overall prevalence at 2 to 3.5 cases per 1000 live births,² and the prevalence is increased among very small premature infants as more have survived. Identification of causal relationships in CP has been challenging. Seventy to 80% of CP cases are acquired prenatally and from largely unknown causes.² Birth complications, including asphyxia, are currently estimated to account for about 10% to 20% of CP cases, but attribution of causation now requires neonatal signs and symptoms consistent with an acute peripartum or intrapartum event sufficient to cause CP³ and evidence of encephalopathy;⁴ global hypoxia-ischemia is not a plausible cause of CP in an infant who did not manifest encephalopathy in the newborn period. In about 10% of patients, CP is acquired postnatally, mainly due to brain damage from bacterial meningitis, viral encephalitis, hyperbilirubinemia, motor vehicle accident, or accidental or non-accidental head trauma.²

Clinical Features

Common manifestations of CSE include alternation of level of consciousness, decreased cognitive function or mental retardation, hypotonia or spasticity or both, global developmental delay or developmental arrest in very severe cases, epilepsy, visual and hearing impairment, and feeding difficulty due to cortical and/or bulbar dysfunction.

For patients with CP, the initial presentation may be hypotonia at birth or during infancy that subsequently evolves to hypertonia, or mixed axial hypotonia and appendicular hypertonia. Some patients may present with motor developmental delay or an abnormal gait. Traditionally, CP has been classified based on the pattern of motor impairment: the spastic (diplegia, quadriplegia, or hemiplegia) type accounts for 70% to 80% of cases, the athetoid or dyskinetic type affects 10% to 20%, and the ataxic type is seen in 5% to 10%.⁵ Mixed-type is used for patients with a combination of symptoms. The effect of CP on functional abilities varies greatly. Some patients are ambulatory with only mild motor deficit, while others are not able to walk. Although CP is defined as a motor disability, other neurological disabilities frequently co-occur in the setting of CP. Intellectual impairment occurs in 30% to 50% of individuals with CP. Mental impairment is more common among those with spastic quadriplegia than in those with other types of CP. About one-half of pediatric patients have seizures. Children with both CP and epilepsy are more likely to have intellectual disability. Speech and language disorders, such as difficulty forming words and speaking clearly, are present in more than one third of individuals with CP. Growth problems are common, as well as other neurological deficits such as visual and hearing impairment and abnormal sensation.

By definition, CSE and CP are nonprogressive, but progressive joint contractures can cause deterioration of motor function. Poorly controlled epilepsy resulting from the brain injury can cause regression of motor and cognitive function. On the other hand, many slowly progressive conditions sometimes are misdiagnosed as CSE or CP.

Diagnosis

Laboratory tests are not necessary to confirm the diagnosis of CSE or CP, as it is based on the history and examination. Diagnostic testing such as brain MRI or genetic testing will help to identify the underlying etiology. Detailed prenatal and perinatal history is critical, and essential criteria need to be met to attribute causal link to birth asphyxia.³

Management

Optimal management of individuals with CSE or CP requires a multidisciplinary approach involving neurologists, rehabilitation medicine specialists, orthopedics, and neurosurgery. Clear objectives and goals should be set before initiation of pharmacological and surgical intervention. Physical therapy and occupational therapy complemented by daily home stretching exercises are essential for prevention of joint contractures and promotion of improved motor function. Some individuals with more diffuse spasticity may benefit from pharmacological therapy with medications such as baclofen, Dantrolene, or benzodiazepines, but most of these medications used are off-label for age and indication and should be used only by experienced physicians. CNS depressant side effects may limit the use of these medications. Intrathecal baclofen administration with a surgically implanted pump may improve the effectiveness of the medication with reduced side effects. The baclofen dose can be adjusted with an external handheld programmer. However, there are neurological emergencies associated with baclofen withdrawal from pump malfunction or an empty reservoir. Infection is another potential complications. Botulinum toxin (Botox) type A may reduce spasticity in injected muscles, but the injection needs to be repeated every 3 to 6 months to maintain the beneficial effects. Phenol intramuscular neurolysis can be considered for spasticity involving large muscles or several muscles, but sedation or anesthesia is required due to severe pain at the injection site. Scoliosis and hip dislocation are the most common conditions requiring surgery. Tendon lengthening or transfer can improve passive range motion and reduce deformity. Selective dorsal rhizotomy, a procedure involving laminectomy and then surgical ablation of 70% to 90% of the dorsal or sensory nerve roots, may be beneficial for selected patients, but it may potentially worsen lumbar lordosis a few years later due to laminectomy.

Psychomotor regression (progressive loss of mental and movement abilities) can be caused by identifiable inborn errors of metabolism, neurodegenerative diseases, or unknown causes. The differential diagnosis is broad, but generally these diseases can be divided into three diagnostically useful groups. Group 1 includes disorders that give rise to intoxication, and it encompasses aminoacidopathies, organic acidurias, urea cycle disorders, sugar intolerances, and metal disorders. These disorders frequently present with acute onset of encephalopathy with vomiting, seizures, altered mental status, and cerebral edema. They can occur during the neonatal period or later in life, from infancy to adulthood, and can occur intermittently. Many of these disorders are treatable/manageable and require emergency removal of the toxin by special diets, dialysis, cleansing drugs (chelators), or vitamins. Group 2 includes disorders affecting cytoplasmic and mitochondrial energy processes, such as glycogen storage diseases, fatty acid oxidation disorders, and mitochondrial diseases. These disorders frequently involve the brain, myocardium, liver, and muscles, and common symptoms include failure to thrive, hypoglycemia, lactic academia, cardiomyopathy or conduction defect, myopathy, and progressive encephalopathy. Group 3 involves cellular organelles and complex large molecules, and includes lysosomal, peroxisomal, glycosylation, and cholesterol synthesis defects. Determining whether the disease affects primarily the gray matter or the white matter will help to narrow the differential diagnosis. Early features of gray matter disease are personality change, seizures, and dementia. White matter disease is characterized by motor deficit, spasticity, and blindness due to optic atrophy. Some CNS demyelinating diseases also have peripheral neuropathy. Specific disorders are described below.

Mitochondrial diseases are a heterogeneous group of disorders that arise as a result of mitochondrial dysfunction or depletion, caused by mutation of genes encoded by either nuclear DNA (patients typically present in infancy or early childhood) or mitochondrial DNA (mtDNA; patients can present at any age). Mitochondrial diseases may affect single organ/tissue only, but often have multisystem involvement, with organs/tissues highly dependent on oxidative aerobic metabolism such as brain, retina, heart, and skeletal muscles preferentially affected.

Clinical Features

The clinical manifestation is extremely variable. Mitochondrial disorders may manifest as recognized clinical syndromes involving multiple organ systems, as in Leber hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Leigh syndrome (subacute necrotizing encephalomyelopathy), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), mitochondrial neurogastrointestinal encephalopathy (MNGIE), and myoclonic epilepsy with ragged red fibers (MERRF). However, many patients have nonspecific manifestation. Infants and children frequently present with hypotonia, weakness, and developmental delay or regression. The constellation of neurological symptoms, optic atrophy, pigmentary retinopathy, external ophthalmoplegia, cardiomyopathy, sensorineural deafness, intestinal pseudo-obstruction, short stature, and diabetes mellitus should raise clinical suspicion of mitochondrial diseases. Other common neurological findings are seizures, dementia, migraine, stroke-like episodes, ataxia, spasticity, myopathy, and exercise intolerance, neuropathy, or neuronopathy. Clinical course may range from an acute life-threatening metabolic derangement or episodic crises (frequently in the setting of febrile illness) with partial recovery to a more gradual progressive neurodevelopmental regression.

Leigh syndrome is a severe and progressive neurometabolic disorder resulting from defects in oxidative phosphorylation or additional steps relating to energy production secondary to mutations in mitochondrial or nuclear DNA. Up to 30 different genes have been identified, and the metabolic defects cause spongy degeneration and necrosis of the basal ganglia and cerebellum. Typically, psychomotor regression develops in an otherwise normal infant in the first year of life, often following a viral illness. Rarely, it occurs in older children and adults. Initial symptoms may be nonspecific, such as failure to thrive and persistent vomiting. Neurological features include hypotonia, feeding and swallowing difficulties, seizures, spasticity, movement disorders, ataxia, ophthalmoplegia, nystagmus, and peripheral neuropathy. Extraneurological manifestations include hypertrophic cardiomyopathy. About 50% of affected individuals die by 3 years of age, often due to respiratory or cardiac failure.

Diagnosis

The diagnosis of mitochondrial diseases is supported by the findings of elevated plasma and/or CSF lactate level. However, spurious elevation of plasma lactate can occur due to poor collection or handling methods or to secondary mitochondrial dysfunction, while a normal lactate level does not exclude the presence of mitochondrial diseases. Quantitative plasma amino acids analysis may show elevated alanine level. Serum ammonia is frequently normal. On brain MRI, nonspecific delayed myelination pattern can be seen in early disease, stroke-like lesions (in a non-vascular distribution, which resolve with minimal atrophy) are suggestive of MELAS, and cerebral and/or cerebellar atrophy with bilateral deep gray lesions are frequently seen in mitochondrial DNA-deletion disorders. Bilateral symmetric hypodensities in the basal ganglia on head CT or bilateral symmetric hyperintense signal abnormality in the dorsal brainstem (periaqueductal gray matter) and/or basal ganglia (specifically the putamen and caudate) on T₂-weighted imaging on MRI of the brain are characteristic features of Leigh syndrome. Magnetic resonance spectroscopy (MRS) may be used to detect an elevated lactate level in brain, which is a nonspecific marker for cellular injury. Molecular genetic testing for mtDNA or nuclear gene mutations is needed. Many patients may not have the diagnosis confirmed by molecular genetic testing from blood, and require further investigation with muscle biopsy for respiratory chain function, analysis for mDNA depletion, mDNA mutation, and duplication/deletion to establish the diagnosis. The classic hallmark of mitochondrial diseases is subsarcolemmal and intermyofibrillar accumulation of mitochondria visualized on Gomori trichrome stain, termed “ragged red fibers.” Genetic testing from leukocytes has replaced biopsy for many of these patients.

Management

Treatment of mitochondrial diseases is primarily supportive, with particular attention to management of feeding and to the airway and ventilation. Therapies to treat specific symptoms and signs of mitochondrial diseases are very important. Seizures are common in patients with CNS involvement and should be treated aggressively to achieve good seizure control. However, it is very important to avoid valproic acid (Depakote or Depakene) because of the significant risk of precipitating and/or accelerating liver disease or other diseases in patients with mitochondria diseases. Insulin and other standard treatments are effective for diabetes mellitus. Vitamins and respiratory chain cofactor (such as succinate, riboflavin, thiamine, and coenzyme Q10) supplements are often recommended for patients with mitochondrial diseases, although much of the evidence comes from case reports and small open-label studies. Supplementation is most useful in patients with specific deficiencies. For example, coenzyme Q10 (CoQ10) supplementation is particularly effective in patients with CoQ10 deficiencies, and individuals with complex I and/or complex II deficiency may benefit from oral administration of riboflavin.

Leukodystrophies (sometimes referred to as white matter diseases) are defined as inherited disorders predominantly affecting the brain white matter, resulting from impaired development (dysmyelination or hypomyelination) or destruction (demyelination) of the myelin sheaths. In some cases, peripheral nerve myelin is also involved. Although individually rare, leukodystrophies comprise of a diverse group of genetic disorders, with an estimated incident of 1 in 7500 live births. The list of defined genetic leukodystrophies is extensive. Among the most common causes of demyelinating leukodystrophies are lysosomal storage diseases (such as metachromatic leukodystrophy and Krabbe disease) and peroxisomal disorders (such as Zellweger [cerebrohepatorenal] syndrome, neonatal adrenoleukodystrophy, and X-linked adrenoleukodystrophy).

Clinical Features

Most patients with leukodystrophies present with motor symptoms, in contrast to primary neuronal disorders (or gray matter diseases) which frequently present with cognitive decline and seizures. CNS demyelination or dysmyelination lead to severe hypotonia during infancy that frequently evolves to axial hypotonia and appendicular hypertonia over time. Some may present with delay acquisition of motor milestones, developmental arrest, or regression of motor function. In older children, the presenting symptoms may be frequent falls or clumsy gait, or decline in sporting skills or other functional skills. Some patients may develop dystonia or movement disorders when deep gray matter is involved, and ataxia when cerebellum is involved. Peripheral neuropathy is seen in Krabbe disease, metachromatic leukodystrophy, adrenoleukodystrophy, and in peroxisomal disorders such as Zellweger syndrome and neonatal adrenoleukodystrophy.

Patients with Zellweger syndrome have characteristic dysmorphic features (high forehead, enlarged fontanelle, and shallow orbits), profound hypotonia, and organomegaly. Other extraneurological findings include adrenal insufficiency in X-linked adrenoleukodystrophy/adrenalmyeloneuropathy and peroxisome biogenesis disorders, hypogonadotropic hypogonadism, growth hormone deficiency and hypothyroidism in 4H leukodystrophy, hypothyroidism in Aicardi-Goutières syndrome, hepatosplenomegaly in certain lysosomal storage diseases, splenomegaly without hepatomegaly in certain peroxisomal disorders, and various ophthalmological findings (such as cataract, retinitis pigmentosa, retinal cherry-red spots, optic atrophy, nystagmus). Cortical visual impairment can be late manifestations of many types of leukodystrophies due to involvement of the cortical visual pathway. In late stages, cognitive decline and seizures may occur.

Diagnosis

The hallmark of leukodystrophy is abnormal white matter on brain MRI. The diagnostic strategy rests upon clinical clues and MRI patterns to guide appropriate metabolic and genetic testing,⁶ complemented by electrophysiological study when a neuropathy is suspected. Extraneurological signs or symptoms provide useful clues for differential diagnosis for specific types of leukodystrophies. The diagnosis of Zellweger syndrome can be made based on finding abnormal ratios of very long-chain fatty acids in blood and cultured fibroblasts, followed by identification of mutations of specific PEX genes which encode different peroxins, the proteins required for normal peroxisome assembly. Specific genetic defects resulting in abnormal enzyme production have been identified for many of the disorders of inborn errors of metabolism (as in peroxisomal disorders or lysosomal disorders), abnormal oligodendrocyte or glia function, or mitochondria dysfunction that are associated with leukodystrophies. However, up to 50% of patients with leukodystrophy do not have identifiable genetic defects.⁷

Management

Treatment is generally supportive. Several types of leukodystrophies have unique complications that require special attentions (such as adrenal insufficiency or Addison disease in X-linked adrenoleukodystrophy/adrenalmyeloneuropathy and peroxisome biogenesis disorders, and cardiac dysfunction in mitochondria disease). Morbidity may be favorably influenced by early recognition and treatment of complications.⁸ In a very few leukodystrophies, primary disease manifestations can be prevented by hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT). However, BMT will not reverse (and may in fact accelerate) deficits. As such, BMT is typically used to treat the pre-symptomatic siblings of index cases.⁸

Lysosomal storage diseases (LSDs) are a group of approximately 50 rare inherited metabolic disorders that result from lysosomal dysfunction, usually as a consequence of deficiency of a vital single enzyme required for the metabolism of lipids, glycoproteins, or mucopolysaccharides. The accumulation of macromolecules results in cellular and tissue dysfunction and symptom development and progression. Classical LSD is classified based on the nature of the accumulating storage material—as in sphingolipidoses, mucopolysaccharidosis, and oligosaccharidoses, and recent classification has expanded to include disorders characterized by defects in synthetic process (such as G3-gangliosideosis), or by trafficking defects (such as Niemann-Pick disease type C1 and C2), as well as by lysosomal membrane diseases (such as Danon disease and action myoclonus-renal failure syndrome).

Clinical Features

The signs and symptoms of LSDs vary depending on disease type, age of onset, and other factors. The constellation of signs and symptoms including dysmorphic features (coarse facies, macroglossia), visual loss and ophthalmologic signs (corneal clouding or macular cherry-red spot), bony abnormalities (dysostosis multiplex), cardiac involvement (arrhythmia or cardiomegaly), hepatosplenomegaly, and progressive neurological symptoms (intellectual disability, developmental delay or development regression, epilepsy, ataxia, hypotonia and/or spasticity, peripheral neuropathy) should prompt consideration of LSD.

Gangliosidoses are autosomal recessive LSDs that can present at any time from fetal life (as ascites and anasarca detected on ultrasound) through adulthood. They are classified according to the predominant stored glycosphingolipid—either GM₁ or GM₂ ganglioside (GM₃ gangliosidosis is a disputed entity, rarely reported). Defective activity of lysosomal hydrolases (β-galactosidase in GM₁ gangliosidosis and hexosaminidase A or B in GM₂ gangliosidosis) results in the progressive accumulation of gangliosides and subsequent dysfunction in the brain and peripheral tissues. Infantile GM₁ gangliosidosis is characterized by coarse facial features, frontal bossing, low-set ears, hepatosplenomegaly, visual impairment, and dysostosis; the phenotype is attenuated in later-onset forms. Hypotonia, profound developmental delay, and seizures are common. Hypotonia, progressive macrocephaly, and developmental regression commonly develop in infants with GM₂ gangliosidosis beginning at 4 to 6 months of age, with death ensuing in most cases by 2 to 4 years. The form of infantile GM₂ gangliosidosis caused by hexosaminidase A deficiency (Tay-Sachs disease) was formerly most frequent in Ashkenazi Jews, but the implementation of a successful screening program has led to a 90% reduction in the frequency of cases in this at-risk population. Similar, albeit much more rare, phenotypes are caused by mutations in different genes causing combined hexosaminidase A and B deficiency (Sandhoff disease) or activator protein deficiency.

Diagnosis

Diagnosis of LSD can be made by demonstrating lysosomal enzyme deficiency in peripheral white blood cells, or fibroblasts, and in the case of Tay-Sachs disease, screening for the common Ashkenazi mutations in HEXA is available. Urine can be screened for excretion of substrates (oligosaccharides for oligosaccharidoses and glycosaminoglycans for mucopolysaccharidoses). Amniotic cells and chorionic villus biopsy can be used for prenatal diagnosis in selected cases. The diagnosis of specific types of LSD is confirmed by genetic testing.

Management

Some LSDs can be efficiently treated by substrate reduction therapies or enzyme replacement therapy (ERT), although ERT has been largely unsuccessful in improving CNS symptoms in neuronopathic forms of lysosomal diseases, likely due to difficulty in getting the enzymes to penetrate the blood–brain barrier. Increasing data suggest that HSCT might be effective in preventing progression of neurological symptoms in individuals with asymptomatic Krabbe disease and may have some efficacy in patients with Hurler disease.^9,10

Congenital disorders of glycosylation (CDG, previously called carbohydrate-deficient glycoprotein syndromes) is a fast-growing group of inherited metabolic disorders characterized by defective activity of enzymes involved in glycosylation—the process of adding complex sugar chains to proteins and lipids. Nearly 70 genetic disorders of glycosylation have been discovered. Based on the metabolic pathway affected, this group of disorder is subdivided into disorder of protein N-glycosylation, disorder of protein O-glycosylation, disorder of multiple glycosylation, and disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation.¹¹

Clinical Features

Clinical presentation and course are highly variable, ranging from death in the first year of life to mildly involved adults. The diagnosis should be considered in an infant or child with developmental delay and hypotonia in combination with multiorgan involvement affecting the nervous system, muscle function, immunity, endocrine system, and coagulation. Typical symptoms and findings include feeding problems, failure to thrive, abnormal liver function, coagulopathy, hypothyroidism, hypogonadism, pericardial effusion or cardiomyopathy, abnormal fat deposits (subcutaneous fat pad) and inverted nipples, seizures, stroke-like episodes, and cerebellar hypoplasia/atrophy and small brainstem.

Diagnosis

The diagnosis of CDG should be considered for any patient with multisystem disease. Cerebellar atrophy is frequently demonstrated on brain MRI. Measurement of selected glycoconjugates can be used to screen for these disorders. A characteristic abnormal isoelectric focusing profile of plasma transferrin or an abnormal glycan profile is typically observed in type I and type II CDG, respectively. Genetic testing is required to confirm the diagnosis and to determine the subtype of CDG.

Management

Current treatment for CDG is supportive but CDG-Ib can be treated with mannose, and some patients with CDG-IIc can be treated with fructose.