Version May 2024
INTRODUCTION — Newborns with neuromuscular disorders often present with hypotonia and weakness. These disorders are caused by a variety of systemic conditions and neurologic disorders that affect the central nervous system (brain or spinal cord), peripheral nervous system, or skeletal muscle [1]. Disorders that affect the last two sites are reviewed briefly here (table 1).
Central nervous system disorders caused by upper motor neuron lesions that involve the descending motor tracts within the brain and spinal cord and other systemic conditions that cause weakness in infants (eg, cerebral palsy, Prader-Willi syndrome, Angelman syndrome, and multiple minor congenital anomaly syndromes) are presented elsewhere. (See "Cerebral palsy: Classification and clinical features" and "Prader-Willi syndrome: Clinical features and diagnosis" and "Congenital cytogenetic abnormalities".)
The assessment of weakness and hypotonia in infants is discussed separately. (See "Approach to the infant with hypotonia and weakness".)
ANTERIOR HORN CELL DISORDERS — Many conditions are caused by degeneration of the anterior horn cells of the spinal cord. They include spinal muscular atrophy, traumatic myelopathy, hypoxic-ischemic myelopathy, and neurogenic arthrogryposis.
Spinal muscular atrophy — The most common and severe type that presents in newborns is spinal muscular atrophy (SMA) type 1, also known as Werdnig-Hoffmann disease. This condition should be suspected in infants with diffuse symmetric proximal muscle weakness that is greater in the lower than upper limbs and absent or markedly decreased deep tendon reflexes. SMA types 2 and 3 have later onset and are less severe. (See "Spinal muscular atrophy".)
Traumatic myelopathy — Myelopathy caused by trauma to the high cervical spinal cord is a rare cause of hypotonia in infants. This condition results in a flaccid paralysis, which may be asymmetric, and absent reflexes. Physical examination may reveal evidence of trauma, such as bruising or fractures. If no accompanying brain injury is present, the infant will be alert with no cranial nerve abnormalities. A pin prick on the face will elicit a facial grimace but no response below the neck. A useful sign is withdrawal to a noxious stimulus of a limb with no spontaneous activity. Bladder distension, priapism, and absence of sweating below the level of the spinal lesion typically will appear as the myelopathy evolves over several days.
Hypoxic-ischemic myelopathy — Severe hypoxic-ischemic injury occasionally can result in hypotonia or flaccid paralysis with diminished or absent reflexes. Affected infants typically have encephalopathy and may have seizures or other signs of end-organ damage. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)
Arthrogryposis multiplex congenita — Arthrogryposis (joint contractures) multiplex congenita is a heterogeneous group of disorders characterized by contractures of multiple joints and degeneration of motor neurons. Most cases are neurogenic; the remainder result from primary muscle disease. (See "Spinal muscular atrophy", section on 'Arthrogryposis multiplex congenita'.)
CONGENITAL NEUROPATHIES — Congenital motor or sensory neuropathies can cause hypotonia and weakness that present during the neonatal period or early infancy. The most important of these conditions are the congenital motor sensory neuropathies and the hereditary sensory and autonomic neuropathies.
Congenital motor sensory neuropathies — Congenital (hereditary) motor and sensory neuropathies comprise a heterogeneous group of disorders that affect the peripheral nervous system. These disorders represent a spectrum of diseases caused by mutations in one of several myelin genes that result in defects in myelin structure, maintenance, or formation. Charcot-Marie-Tooth disease is the most common of these conditions. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis".)
Hereditary sensory and autonomic neuropathies — Hereditary sensory and autonomic neuropathies are a group of rare disorders that selectively affect peripheral sensory and autonomic neurons (table 2). They present in infancy and result in a variable extent of autonomic dysfunction or insensitivity to pain and temperature. The most common hereditary sensory and autonomic neuropathy is familial dysautonomia (Riley-Day syndrome). (See "Hereditary sensory and autonomic neuropathies".)
NEUROMUSCULAR JUNCTION DISORDERS — Disorders of the neuromuscular junction are characterized by abnormal neuromuscular transmission, leading to muscle fatigability and weakness. These rare conditions include transient acquired neonatal myasthenia, congenital myasthenia, toxicity caused by magnesium or aminoglycosides, and infant botulism. Although most of these disorders are transient, congenital forms sometimes may be permanent. (See "Neuromuscular junction disorders in newborns and infants".)
CONGENITAL MYOPATHIES — Congenital myopathies are primary muscle disorders that are present from birth, although their expression may be delayed until later in infancy or childhood. They present with hypotonia and weakness that is greater proximally than distally. The most common diseases are nemaline myopathy, central core disease, myotubular myopathy, congenital fiber type disproportion, and multicore myopathy. (See "Congenital myopathies".)
MUSCULAR DYSTROPHIES — The muscular dystrophies are an inherited group of progressive myopathic disorders resulting from defects in numerous genes required for normal muscle function. Some present in the newborn period (table 1).
Dystrophinopathies — The Duchenne and Becker muscular dystrophies are caused by mutations of the dystrophin gene and, therefore, are named dystrophinopathies. Although histologic and laboratory evidence of a myopathy may be observed from birth among male children with Duchenne muscular dystrophy, the clinical onset of weakness usually occurs between two and three years of age, or later. The age of onset of symptoms usually is later and the degree of clinical involvement milder in Becker than Duchenne muscular dystrophy. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)
Congenital muscular dystrophies — Congenital muscular dystrophies include a number of conditions in which infants are hypotonic and weak at birth and in which muscle biopsies show changes consistent with muscular dystrophy. Arthrogryposis (joint contractures) commonly is observed in the newborn period. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Congenital muscular dystrophies'.)
These disorders are classified according to the association with brain malformations and the presence or absence of merosin (a component of the dystrophin-associated protein complex) deficiency. Types associated with brain malformations include Fukuyama type, Walker-Warburg syndrome, and muscle-eye-brain disease. Walker-Warburg syndrome and muscle-eye-brain disease may be due to congenital defects in post-translational protein glycosylation, although genetic heterogeneity has been reported.
Facioscapulohumeral muscular dystrophy — Onset of the classical form of this disorder usually is in the second or third decade, and progression typically is slow. However, the infantile form has an earlier onset (usually within the first few years of life) and is rapidly progressive. (See "Facioscapulohumeral muscular dystrophy", section on 'Infantile form'.)
Congenital myotonic dystrophy — The classic form of myotonic dystrophy has its onset in adolescence or adulthood. The congenital form of the disease occurs in infants born to mothers with myotonic dystrophy. Patients may present with profound hypotonia at birth occurring in association with facial diplegia, feeding, respiratory difficulties, and skeletal deformities such as clubfeet. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Congenital DM1'.)
INBORN ERRORS OF METABOLISM — Certain inborn errors of metabolism can present with progressive muscular hypotonia and weakness and/or acute muscle dysfunction with acute muscle breakdown (rhabdomyolysis) or myoglobinuria. These conditions include disorders of glycogen, glycosylation, lipid, peroxisomal, creatine, and mitochondrial metabolism. (See "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)
Disorders of glycogen metabolism — Among the disorders of glycogen metabolism, only acid maltase deficiency (Pompe disease) typically affects newborns. This condition results in accumulation of glycogen within the lysosomes of tissues, including anterior horn cells of the spinal cord, skeletal muscles, brain, heart, and liver. Affected infants usually develop hypotonia and weakness in the first few weeks after birth, as well as significant cardiomegaly, moderate hepatomegaly, and macroglossia. Early diagnosis of Pompe disease is essential, as specific enzyme replacement therapy is available and appears to benefit affected infants. (See "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)".)
Other abnormalities of glycogen metabolism, such as phosphorylase b kinase deficiency, phosphoglycerate kinase deficiency, and branching enzyme deficiency, typically present later in childhood but can present with hypotonia in infancy. (See "Overview of inherited disorders of glucose and glycogen metabolism".)
Primary carnitine deficiency — Primary systemic carnitine deficiency is a disorder of fatty acid oxidation caused by a deficiency of the organic cation/carnitine transporter in the plasma membrane, resulting in defective transport of carnitine from plasma into the cells of affected tissues. This condition typically presents in late infancy or early childhood but can present in the newborn period with weakness, hypotonia, and cardiomyopathy. (See "Specific fatty acid oxidation disorders", section on 'Carnitine transporter deficiency'.)
Peroxisomal disorders — Peroxisomal disorders can present during the neonatal period with profound hypotonia and weakness. Signs include central nervous system dysfunction, facial dysmorphism (as in Zellweger syndrome), hepatomegaly, cataracts, retinopathy, calcific stippling of epiphyses, and rhizomelia. (See "Peroxisomal disorders".)
Disorders of creatine metabolism — Disorders of creatine metabolism encompass three distinct inborn errors of metabolism [2,3]:
●Guanidinoacetate methyltransferase (GAMT) deficiency [4]
●Arginine-glycine amidinotransferase (AGAT) deficiency
●Creatine transporter (CRTR) deficiency
Clinical features include muscular hypotonia, epilepsy, extrapyramidal symptoms, and developmental delay. Creatine supplementation and dietary intervention may benefit patients with GAMT and AGAT deficiencies [2,4].
Mitochondrial myopathies — Mitochondrial myopathies consist of primary abnormalities of mitochondrial structure and function with an associated involvement of muscle. They are caused by defects of substrate transport, substrate utilization (including the citric acid cycle), and the respiratory chain (oxidative phosphorylation coupling). Respiratory chain abnormalities are most likely to lead to prominent muscle disease in the newborn. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism" and "Mitochondrial myopathies: Clinical features and diagnosis".)
Mitochondrial myopathy should be suspected in an infant with weakness and lactic acidosis, especially if multisystem involvement is present.
Cytochrome c oxidase deficiency — Cytochrome c oxidase (COX, complex IV) deficiency is the most common respiratory chain disorder causing myopathy in newborns [5,6]. The enzyme deficiency results in impairment of energy production. Affected patients present within the first days or weeks with profound generalized weakness, hypotonia, hyporeflexia, poor feeding, respiratory difficulty, and lactic acidosis (caused by decreased utilization of pyruvate, which is then converted to lactate). They also may have macroglossia, hepatomegaly, and cardiomyopathy. The disease is fatal within a few months. Some of these individuals have renal defects (de Toni-Debré-Fanconi syndrome) with impaired proximal tubular function that may lead to glucosuria, tubular proteinuria (including generalized amino aciduria), renal tubular acidosis, hypokalemia, and hypouricemia.
Cytochrome c oxidase deficiency also can result in a reversible myopathy caused by a maternally inherited mutations (m.14674T>C or m.14674T>G) involving the mitochondrial transfer RNA for glutamic acid [7-11]. The presentation of this condition is similar to that of the severe neonatal form. The condition is life-threatening in the first months after birth. Thereafter, infants improve biochemically and clinically over one to two years.
Other presentations of cytochrome c oxidase deficiency have a more prominent encephalopathic component (eg, Leigh syndrome) [12,13]. (See "Neuropathies associated with hereditary disorders", section on 'Leigh syndrome'.)
Cytochrome c oxidase deficiency is associated with pathologic mutations in more than 30 genes involving both mitochondrial and nuclear DNA [14].
The serum creatine kinase concentration may be slightly elevated in this disorder, although the electromyography usually is normal. Muscle biopsy shows nonspecific myopathic changes and ragged red fibers on Gomori trichrome staining, which is strong evidence for mitochondrial disease. Deficiency of cytochrome c oxidase is apparent on histochemical staining. Electron microscopy reveals accumulation of lipid and glycogen and an increased number of large abnormal appearing mitochondria in the muscle fibers. The severe and benign conditions can be differentiated on muscle biopsy.
SUMMARY
●Anterior horn cell disorders – Degeneration of the anterior horn cells of the spinal cord can occur in spinal muscular atrophy, traumatic myelopathy, hypoxic-ischemic myelopathy, and neurogenic arthrogryposis. (See 'Anterior horn cell disorders' above.)
●Congenital neuropathies – Congenital neuropathies can cause hypotonia and weakness that present during the neonatal period or early infancy. The most important of these conditions are the congenital motor sensory neuropathies and the hereditary sensory and autonomic neuropathies. (See 'Congenital neuropathies' above.)
●Neuromuscular junction disorders – Disorders of the neuromuscular junction are characterized by abnormal neuromuscular transmission, leading to muscle fatigability and weakness. These rare conditions include transient acquired neonatal myasthenia, congenital myasthenia, toxicity caused by magnesium or aminoglycosides, and infant botulism. (See "Neuromuscular junction disorders in newborns and infants".)
●Congenital myopathies – Congenital myopathies are primary muscle disorders that are present from birth, although their expression may be delayed until later in infancy or childhood. They present with hypotonia and weakness that is greater proximally than distally. The most common diseases are nemaline myopathy, central core disease, myotubular myopathy, congenital fiber type disproportion, and multicore myopathy. (See "Congenital myopathies".)
●Muscular dystrophies – The muscular dystrophies are an inherited group of progressive myopathic disorders resulting from defects in numerous genes required for normal muscle function. Some present in the newborn period (table 1). (See 'Muscular dystrophies' above.)
●Inborn errors of metabolism – Certain inborn errors of metabolism can present with progressive muscular hypotonia and weakness and/or acute muscle dysfunction with muscle breakdown or myoglobinuria. These conditions include disorders of glycogen, lipid, peroxisomal, creatine, and mitochondrial metabolism. (See 'Inborn errors of metabolism' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Geoffrey Miller, MD, who contributed to earlier versions of this topic review.
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