Table 4.

Genetic Disorders with Hypotonia in Infancy in the Differential Diagnosis of Prader-Willi Syndrome

DisorderGene(s)MOIClinical Features / Comment
Angelman syndrome (AS)UBE3A 1Recurrence risk is mechanism dependent. 2Severe DD or ID, severe speech impairment, gait ataxia &/or tremulousness of the limbs, & unique behavior w/happy demeanor, frequent laughing, smiling, & excitability. Microcephaly & seizures are common. Hypotonia may be the only manifestation of AS in infancy. Affected persons lack characteristic sucking issues, hypogonadism, & facial appearance of those w/PWS.
Congenital myasthenic syndromes (CMS)>30 genes incl:
CHAT
CHRNE
COL13A1
COLQ
DOK7
RAPSN
AR
AD 3
Typically presents w/fatigable weakness involving ocular, bulbar, & limb muscles w/onset typically age <2 yrs. In the classic presentation, a CMS is limited to weakness of skeletal muscles.
Congenital myotonic dystrophy type 1 DMPK ADHypotonia & severe generalized weakness at birth, often w/respiratory insufficiency & early death; ID is common.
Fragile X syndrome (See FMR1 Disorders.) FMR1 XLModerate ID in affected males & mild ID in affected females. Males may have a characteristic appearance, connective tissue findings, & large testes (post pubertal). Behavioral abnormalities are common. Hypotonia may be the only manifestation in infancy. Affected persons lack characteristic sucking issues, hypogonadism, & facial appearance of those w/PWS.
GARS1 infantile-onset SMA (See GARS1-Assoc Axonal Neuropathy.) GARS1 ADInitial manifestations are typically respiratory distress, poor feeding, & muscle weakness (distal > proximal).
Infantile-onset Pompe disease GAA AROnset is typically at median age of 4 mos w/hypotonia, generalized muscle weakness, feeding difficulties, poor weight gain, respiratory distress, & hypertrophic cardiomyopathy. (Note: In PWS, hypotonia is noted at birth, not several months later.)
Schaaf-Yang syndrome MAGEL2 AD w/imprinting 4Hypotonia & feeding difficulties in infancy are similar to PWS, but joint contractures incl arthrogryposis are features not typical of PWS. ASD is frequent as well as ID, which can be profound. Some persons develop obesity & hyperphagia in late childhood/adolescence that ↑ w/age.
Spinal muscular atrophy SMN1 ARPoor respiratory effort may be present, a feature rarely seen in PWS.
WAC-related ID WAC ADVariable degrees of DD &/or ID. Behavioral abnormalities are observed in the majority of older children & adults. Most affected infants have significant but nonspecific features at birth (e.g., neonatal hypotonia, feeding issues).
X-linked infantile SMA UBA1 XLCongenital hypotonia, areflexia, & evidence of degeneration & loss of anterior horn cells (i.e., lower motor neurons) in spinal cord & brain stem. Often congenital contractures &/or fractures are present.
Zellweger spectrum disorder (ZSD)ZSD-PEX genesAR 5Affected newborns are hypotonic w/poor feeding. They have distinctive facies, congenital malformations, & liver disease that can be severe. (Note: The brain MRI findings are very striking & distinctive in ZSD, while the brain MRIs of persons w/PWS are typically relatively normal.)

AD = autosomal dominant; AR = autosomal recessive; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PWS = Prader-Willi syndrome; SMA = spinal muscular atrophy; XL = X-linked

1.

Angelman syndrome (AS) is associated with deficient expression or function of the maternally inherited UBE3A allele, which can be caused by a variety of different mechanisms.

2.

Individuals with AS typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a de novo genetic alteration associated with a very low recurrence. Less commonly, an individual with AS has the disorder as the result of a genetic alteration associated with an imprinting pattern of autosomal dominant inheritance or variable recurrence risk.

3.

Congenital myasthenic syndromes (CMS) are typically inherited in an autosomal recessive manner. Less commonly, CMS are inherited in an autosomal dominant manner.

4.

Schaaf-Yang syndrome is inherited in an autosomal dominant imprinted manner (a heterozygous pathogenic variant on the paternally derived MAGEL2 allele results in disease).

5.

Zellweger spectrum disorder (ZSD) is typically inherited in an autosomal recessive manner (one PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state).

From: Prader-Willi Syndrome

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