Common Genetic Disorders for Which Neuromotor Delays May Be a Presenting Feature

ConditionInheritanceClinical TestingClinical Caveats
Angelman syndromeSporadicMethylation testing for Prader-Willi/Angelman syndrome critical region, gene sequencing of UBE3A geneInfantile hypotonia and delayed motor milestones, usually present with global delays; dysmorphic features are subtle in infancy.
Chromosome disordersMany sporadic; high recurrence risk for unbalanced translocations if 1 parent has a balanced translocationChromosome analysis, single nucleotide polymorphism microarraySome patients will have multiple anomalies and will have global developmental delays. Some may present in infancy or early childhood with delayed motor and/or speech milestones.
Down syndromeChromosome mosaicism also seen.
Klinefelter syndrome
Rare deletions and duplications
Deletion 22q11 syndrome (velocardiofacial syndrome)Autosomal dominant (most cases new mutations)Fluorescence in situ hybridization (FISH) for deletion 22q11.290% of cases new mutations. Feeding and speech disorders and cognitive impairment also seen. >50% will have a congenital heart defect.
DMDX-linked recessiveCK, sequencing of dystrophin geneBecker and Duchenne muscular dystrophies are caused by mutations in different regions of the dystrophin gene. Becker muscular dystrophy has a later onset of symptoms with a less severe course; 67% of cases are inherited, 33% are new mutations.
Becker muscular dystrophy
Fragile X syndromeX-linkedGene sequencing and methylation analysis of FMR1 geneUsually have global delays and cognitive impairment but may present in infancy or early childhood with predominantly motor delays. Males affected primarily, but females with FMR1 expansions may also be affected.
Mitochondrial myopathiesAutosomal recessive;Constitutional and mitochondrial genetic testing, lactate/pyruvate levels and ratio, serum amino acidsGenetic heterogeneity. May not present in infancy. Also at risk for cardiomyopathy, vision loss, hearing loss, cognitive disabilities.
X-linked recessive
mitochondrial inheritance
Myotonic muscular dystrophyAutosomal dominantGene sequencing for DMPK geneMay see anticipation with progression of phenotype in subsequent generations.
Neurofibromatosis type 1 (NF1)Autosomal dominantUsually a clinical diagnosis, gene sequencing NF1 gene50% new mutations. Hypotonia most evident in infancy and early childhood. Suspect NF1 if hypotonia seen with multiple café au lait spots.
Noonan syndromeAutosomal dominantGene sequencing for PTPN11 gene, genetically heterogeneous and multiple gene sequencing panels are availableGenetic heterogeneity. Commonly associated with short stature, ptosis, learning and developmental delays, hypotonia, pulmonary stenosis, cryptorchidism, cardiomyopathy.
Prader-Willi syndromeSporadicDNA methylation testing for Prader-Willi/Angelman syndrome critical regionHypogonadism, especially in boys. Hypotonia most evident in infancy and may be profound.
Spinal muscular atrophy, including congenital axonal neuropathy, Werdnig-Hoffmann disease, Kugelberg-Welander diseaseAutosomal recessiveGene deletion or truncation studies for SMN1 gene (95% to 98% of cases)Usually presents in early infancy with severe hypotonia. Milder forms identified at later ages.