Table 3b.

Non-Amyloidotic Neuropathies to Consider in the Differential Diagnosis of Hereditary Transthyretin (ATTR) Amyloidosis

DiffDx DisorderGeneMOIClinical Features of DiffDx Disorder
Charcot-Marie-Tooth hereditary neuropathy Many 1AD
Present w/peripheral neuropathy
  • No cardiomyopathy
  • Disease progression is slower than in hereditary ATTR amyloidosis.
Fabry disease GLA XLPresent w/cardiomyopathy, nephropathy, & peripheral nephropathy
  • Juvenile onset, esp in males
  • Angiokeratoma
  • ↓ α galactosidase activity
Mitochondrial disorders incl MELAS (See Mitochondrial Disorders Overview.)Many 2Mat
  • Present w/cardiomyopathy
  • Neuropathy &/or nephropathy variably present
  • Myopathy
  • Diabetes
  • Deafness
  • ↑ serum lactate & pyruvate levels
Hereditary hypertrophic cardiomyopathy Many 3ADPresent w/cardiomyopathyNo peripheral/autonomic neuropathy
Cardiac sarcoidosisNA
(acquired disorders)
  • Present w/cardiomyopathy
  • Peripheral neuropathy &/or nephropathy variably present
  • Negative family history
  • Uveitis
  • Hilar lymphadenopathy
  • ↑ serum angiotensin-converting enzyme level
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)Present w/peripheral neuropathy
  • Negative family history
  • No cardiomyopathy
  • Most common misdiagnosis in those w/ATTR amyloidosis 4
Crow-Fukase syndrome (aka POEMS)
  • Negative family history
  • Positive serum &/or urine monoclonal protein
  • ↑ serum vascular endothelial growth factor level
Diabetic neuropathy
  • Negative family history
  • ↑ blood sugar level

↑ = high; ↓ = low; AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; Mat = maternal; MOI = mode of inheritance; POEMS = plasma cell neoplasia w/polyneuropathy, organomegaly, endocrinopathy, M protein, & skin changes; NA = not applicable; XL = X-linked


More than 80 different genes are associated with CMT [Stojkovic 2016].


Pathogenic variants known to cause MELAS have been identified in mtDNA tRNA genes including MT-TL-1, MT-ND5, MT-TC, MT-TK, MT-TV, MT-TF, MT-TQ, MT-TS1, MT-TS2, and MT-TW, and in the protein-encoding genes MT-CO1, MT-CO2, MT-CO3, MT-CYB, MT-ND1, MT-ND3, and MT-ND6. Pathogenic variants in many other genes cause mitochondrial disorders (see Mitochondrial Disorders Overview).


Pathogenic variants known to cause hereditary hypertrophic cardiomyopathy have been identified in MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, CSRP3, ACTN2, MYH6, TCAP, TNNC1, PLN, MYOZ2, and NEXN (see Hypertrophic Cardiomyopathy Overview).


18/90 individuals with hereditary ATTR amyloidosis without a family history were mistakenly diagnosed with CIDP [Planté-Bordeneuve et al 2007].

From: Hereditary Transthyretin Amyloidosis

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