Penetrance

Penetrance in previously reported families with known recurrences is high for DYNC1H1-related disorders . It is assumed that penetrance is age-related because of observed disease progression over time .

Source: GeneReviews — "DYNC1H1-Related Disorders"

Diagnostic Criteria

Suggestive Findings

A DYNC1H1-related disorder should be considered in a proband with the following age-related clinical and electrophysiologic findings of axonal neuropathy with or without developmental delay/ intellectual disability and related central nervous findings, as well as family history.

DYNC1H1-Related Neuromuscular Disorder (DYNC1H1-NMD)

Axonal neuropathy. At all ages across the phenotypic spectrum of DYNC1H1-related disorders:

• Muscle weakness and reduced-to-absent reflexes that can manifest:

• Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures;

• In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength.

Source: GeneReviews — "DYNC1H1-Related Disorders"

Differential Diagnosis

Because DYNC1H1-related disorders are clinically indistinguishable from many other inherited disorders with similar neurologic findings, diagnosing this condition on clinical grounds only without molecular genetic testing is not feasible. All disorders with neuromuscular and/or neurodevelopmental features without other distinctive findings should be considered in the differential diagnosis. See: • Charcot-Marie-Tooth Hereditary Neuropathy Overview • OMIM Phenotypic Series: • Autosomal dominant intellectual developmental disorder • Autosomal recessive intellectual developmental disorder • Nonsyndromic X-linked intellectual developmental disorder • Syndromic X-linked intellectual developmental disorder Specific disorders with a high degree of clinical overlap include those listed (DYNC1H1-related neuromuscular disorder) and (DYNC1H1-related neurodevelopmental disorder). Table 4a. DYNC1H1-Related Neuromuscular Disorder: Selected Disorders in the Differential Diagnosis

Management Guidelines

No clinical practice guidelines for DYNC1H1-related disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a DYNC1H1-related disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

DYNC1H1-Related Disorders: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Peripheral neuropathy/

Spinal muscular atrophy

| Neurologic exam | To incl a comprehensive assessment esp of lower extremities:

• Hyporeflexia, muscle tone, strength, atrophy

• Gower sign

Consider:

• NCS/EMG to document presence of motor axonal neuropathy

• Muscle MRI for identifying atrophy, fatty replacement, /or compensatory hypertrophy

Musculoskeletal

| Orthopedics/ physical medicine rehab/ PT OT eval | To incl assessment of:

• Gross motor fine motor skills

• Foot deformities, limb contractures, spine deformities, hip dysplasia

• Mobility, ADL, need for adaptive devices

• Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills)

CNS involvement

| By pediatric neurologist/ developmental pediatrician | To incl assessment of:

Source: GeneReviews — "DYNC1H1-Related Disorders"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 7. DYNC1H1-Related Disorders: Recommended Surveillance

Source: GeneReviews — "DYNC1H1-Related Disorders"