Conditions that result in hypotonia of muscle

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Conditions Causing Hypotonia

Hypotonia (decreased resistance of muscles to passive manipulation - the "floppy" state) results from lesions at any level from the cerebral cortex down to the muscle itself. The anatomical level of the lesion determines the clinical pattern.

Key Clinical Distinction: Central vs. Peripheral Hypotonia

Feature	Central (Upper Motor Neuron)	Peripheral (Lower Motor Neuron / NMJ / Muscle)
Weakness	Axial > appendicular	Profound, often appendicular
Reflexes	Preserved or increased over time	Absent or reduced
Alertness	Often impaired	Alert, awake
CK	Normal	Normal to markedly elevated
Other	Dysmorphic features common	Fasciculations (SMA)

Central disorders are far more common causes of hypotonia than motor unit diseases. - Bradley and Daroff's Neurology in Clinical Practice

I. Central (Cerebral) Hypotonia

Lesions at the cerebral hemisphere level produce hypotonia disproportionate to the degree of weakness, often with concurrent axial hypotonia + appendicular hypertonia.

A. Chromosomal Disorders

Prader-Willi Syndrome (PWS) - absence of paternally expressed genes on chromosome 15q; profound hypotonia, poor feeding; normal CK, EMG, and muscle biopsy. Diagnosed by DNA methylation analysis (targets SNURF-SNRPN locus).
Down Syndrome (Trisomy 21) - hypotonia is a cardinal feature
Angelman Syndrome - chromosome 15 imprinting disorder
Other microdeletion/microduplication syndromes (detected by array CGH)

B. Perinatal Brain Injury

Hypoxic-ischemic encephalopathy (HIE) - most common acquired cause of neonatal hypotonia; acquired perinatal injury is far more common than inherited disorders
Periventricular leukomalacia
Intracranial hemorrhage

C. Chronic Nonprogressive Encephalopathy (Cerebral Palsy)

Cerebral dysgenesis related to genetic disorder
In utero infection (TORCH)
Toxic exposure
Inborn error of metabolism
Vascular insult

D. Cerebellar Disease

Loss of the deep cerebellar nuclei (particularly dentate and interposed nuclei) causes hypotonia on the ipsilateral side. The mechanism is loss of cerebellar facilitation of motor cortex and brainstem motor nuclei by tonic signals. Hypotonia is more apparent in acute than chronic cerebellar lesions. - Guyton and Hall Medical Physiology, Adams and Victor's Neurology

E. Metabolic / Endocrine

Hypothyroidism - TSH should be checked in any infant with hypotonia
Peroxisomal disorders (Zellweger syndrome, neonatal adrenoleukodystrophy)
Mitochondrial disorders

II. Combined Cerebral and Motor Unit Disorders

These conditions affect both the CNS and the peripheral neuromuscular system:

Condition	Key Features
Acid maltase deficiency (Pompe disease)	Lysosomal glycogen accumulation; severe skeletal myopathy + cardiomyopathy + encephalopathy; diagnosed by acid α-1,4-glucosidase assay; enzyme replacement available
Congenital Myotonic Dystrophy	Autosomal dominant (DMPK trinucleotide repeat); ~25% of infants of affected mothers; profound hypotonia + facial weakness; survivors develop myotonia at puberty
Syndromic Congenital Muscular Dystrophies	Defects of O-glycosylation of dystroglycan; Fukuyama CMD, Walker-Warburg syndrome, muscle-eye-brain disease; hypotonia + epilepsy + cobblestone lissencephaly + ocular defects
Congenital Disorders of Glycosylation	Type Ia (phosphomannomutase deficiency) most common; hypotonia + hyporeflexia + inverted nipples + abnormal fat distribution
Lysosomal Disorders	Multiple types
Infantile Neuroaxonal Dystrophy	PLA2G6 mutations

III. Spinal Cord Disorders

Condition	Key Features
Spinal Muscular Atrophy (SMA)	Anterior horn cell degeneration; SMN1 deletion; types I-IV; now in newborn screening; tongue fasciculations, paradoxical breathing
X-linked SMA	UBE1 mutations
Infantile SMA with Respiratory Distress	IGHMBP2 mutations
Acquired Spinal Cord Lesions	Trauma, cord compression, ischemia

IV. Peripheral Nerve Disorders

Condition	Key Features
Congenital Hypomyelinating Neuropathy / Dejerine-Sottas Disease	Severe demyelinating neuropathy; absent reflexes; elevated CSF protein; nerve conduction severely reduced
Charcot-Marie-Tooth disease (congenital)	Hereditary motor and sensory neuropathy
Hereditary neuropathies	Various types

V. Neuromuscular Junction (NMJ) Disorders

Condition	Key Features
Neonatal (Transient) Myasthenia Gravis	Maternal anti-AChR antibodies; resolves within weeks
Juvenile Myasthenia Gravis	Autoimmune; anti-AChR or anti-MuSK antibodies; ptosis, fatigable weakness
Congenital Myasthenic Syndromes	Genetic defects in NMJ components; antibody-negative
Infant Botulism	Clostridium botulinum toxin; descending flaccid paralysis, constipation, ophthalmoplegia; ocular palsies and apnea are late signs

VI. Muscle Disorders (Myopathies)

Congenital Myopathies (structural)

Central core disease - RYR1 mutations; malignant hyperthermia risk
Nemaline (rod) myopathy - nemaline rods on Gomori trichrome stain
Centronuclear (myotubular) myopathy - X-linked or AD/AR; centrally placed nuclei

Congenital Muscular Dystrophies

Merosin-deficient CMD (laminin α2 deficiency, LAMA2 mutations) - white matter abnormalities on MRI
Ullrich CMD - collagen VI deficiency; distal joint hyperlaxity + proximal contractures
Infantile Facioscapulohumeral Dystrophy - D4Z4 repeat contraction; may have cognitive impairment, epilepsy, hearing loss

Other Muscle Conditions

Metabolic myopathies - glycogen storage diseases, lipid myopathies
Mitochondrial myopathies - elevated lactate/pyruvate ratio

Diagnostic Approach Summary

Hypotonia
    │
    ├── Central signs (encephalopathy, seizures, dysmorphic features)?
    │       → Brain MRI, karyotype/array CGH, metabolic screen, TSH
    │
    └── Peripheral signs (alert, areflexia, weakness)?
            → Serum CK
                ├── Normal/mildly elevated → EMG/NCS
                │       ├── Neuropathic → SMA (SMN1 deletion), nerve biopsy
                │       ├── Myopathic → Muscle biopsy, gene panel
                │       └── NMJ pattern → AChR antibodies, repetitive nerve stim
                └── Markedly elevated → Muscular dystrophy, myopathy

Key workup tests: serum CK, TSH, lactate/pyruvate, array CGH, SMN1 deletion analysis (SMA), EMG/NCS, muscle biopsy, brain MRI, AChR/MuSK antibodies, enzyme assays (Pompe), whole exome sequencing when above negative.

Sources: Bradley and Daroff's Neurology in Clinical Practice; Adams and Victor's Principles of Neurology, 12th ed.; Guyton and Hall Textbook of Medical Physiology; The Harriet Lane Handbook, 23rd ed.

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