Clinical Guidance

Autosomal dominant MFN2-HMSN. Variants in certain amino acid residues are always pathogenic, with no evidence of reduced penetrance or variable expressivity (range of phenotypic expression) despite different amino acid substitutions. Examples of different missense changes observed at the same conserved amino acid residue include p.Arg94Trp/Gln, p.Arg104Glu/Trp, p.Ser249Thr/Cys, p.Trp740Ser/Arg . In contrast, variants in other amino acid residues are associated with variable expressivity (early vs later onset of disease) dependent on the amino acid substitution at the same residue. Autosomal dominant vs autosomal recessive variants. No significant genotype-phenotype correlations can be made.

Source: GeneReviews — "MFN2 Hereditary Motor and Sensory Neuropathy"

Penetrance

The penetrance for AD MFN2-HMSN is considered to be complete. While some individuals with a heterozygous MFN2 pathogenic variant are asymptomatic and have only mild findings on examination at the time of diagnosis, the disease may prove to be late onset in these instances .

Source: GeneReviews — "MFN2 Hereditary Motor and Sensory Neuropathy"

Diagnostic Criteria

Formal diagnostic criteria for MFN2 hereditary motor and sensory neuropathy have not been established.

Suggestive Findings

MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) should be considered in individuals with the following clinical and neurophysiologic findings. Note: No specific findings distinguish MFN2-HMSN from other inherited hereditary motor and sensory neuropathies.

Clinical findings

• Onset before age ten years (although a wide range has been reported)

• Involvement of the lower extremities earlier and more severely than the upper extremities

• Involvement of the distal upper extremities as the neuropathy progresses

• Motor deficits more prominent than sensory deficits

• Optic atrophy (~7% in the autosomal dominant form, and ~20% in the autosomal recessive form)

Source: GeneReviews — "MFN2 Hereditary Motor and Sensory Neuropathy"

Differential Diagnosis

All hereditary motor and sensory neuropathy (HMSN) forms in which axonal phenotypes have been reported, including PMP22-HMSN, MPZ-HMSN, and GJB1-HMSN (see GJB1 Disorders) need to be considered in the differential diagnosis of MFN2-HMSN. See Charcot-Marie-Tooth Hereditary Neuropathy Overview. MFN2 pathogenic variants are by far the most common cause of autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2). As many as one third of all individuals with CMT2 with a positive family history have a pathogenic variant in MFN2 . Thus, testing of MFN2 is probably the first genetic test to consider in families with an axonal neuropathy demonstrating male-to-male transmission.

Source: GeneReviews — "MFN2 Hereditary Motor and Sensory Neuropathy"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with MFN2 Hereditary Motor and Sensory Neuropathy

Source: GeneReviews — "MFN2 Hereditary Motor and Sensory Neuropathy"

Clinical Guidance

Obesity, which makes walking more difficult, should be avoided. Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website for an up-to-date list.

Source: GeneReviews — "MFN2 Hereditary Motor and Sensory Neuropathy"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "MFN2 Hereditary Motor and Sensory Neuropathy"

Surveillance Guidelines

Table 4. Recommended Surveillance for Individuals with MFN2 Hereditary Motor and Sensory Neuropathy

Source: GeneReviews — "MFN2 Hereditary Motor and Sensory Neuropathy"