Clinical Neurology · Child Neurology

Delayed Milestones — Differentials

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Differential diagnosis of developmental delay, organized by the predominant domain affected.

Cause	Details
Predominant speech delay
Autism spectrum disorders	—
Hearing impairment	—
Congenital bilateral perisylvian syndrome (CBPS)	—
Predominantly motor delay — Brain
Cerebral palsy	Spastic, ataxic, athetoid, dystonic
Predominantly motor delay — Spinal cord
Hereditary spastic paraplegia	SPG (spastic gait genes) mutations, 70 different loci identified; SPG4 (spastin) is the most common 2 peaks at 2 and 40 years Diagnosed by family history and exclusion of other conditions
Primary lateral sclerosis, juvenile variant	ALS2 gene mutation, AR inheritance Begins in early childhood and progresses over 10–15 years
Predominantly motor delay — Anterior horn cells
Spinal muscular atrophy	5q13 deletion — autosomal recessive — proximal weakness & respiratory involvement Type I (Werdnig-Hoffmann, at birth), Type II (Dubowitz, after 6 months), Type III (Kugelberg-Welander, after 1 year) Normally there are two genes at 5q13: SMN1, which encodes most of the SMN protein, and SMN2, which encodes only 10–20% of SMN protein (it has a different nucleotide that makes its protein undergo a variable degree of splicing and degradation). SMA patients have mutated SMN1, so the variation of protein produced by SMN2 gives the variable age of presentation
X-linked spinal muscular atrophy type II (SMAX2)	Similar to SMA type I but different gene mutation. NB: SMAX1 is Kennedy disease, adult onset
Predominantly motor delay — Peripheral nerves
Dejerine-Sottas syndrome (HSMN 3 / CMT 3)	PMP22 or MPZ mutation, onset in infancy, demyelinating
Predominantly motor delay — Muscle disease
Muscular dystrophy	Duchenne — Becker — congenital myopathies (Fukuyama — merosin deficient)
Muscle channelopathy	Myotonia congenita (ClCN, AR, less severe, at 4–6 years) Thomsen disease (SCN4A, AD, severe, at birth) Paramyotonia congenita (worse with exercise, SCN4A, AD)
Mitochondrial disease	MELAS — MERRF
Global delay
Cerebral malformations	—
Chromosomal abnormalities	—
Intrauterine infection	—
Perinatal disorders	—
Metabolic progressive encephalopathies	Amino acid Lysosomal enzymes Glycogen storage Mitochondrial disorders Leukodystrophies

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