The diagnosis of HSAN I is based on the observation of symptoms described above and is supported by a family history suggesting autosomal dominant inheritance. The diagnosis is also supported by additional tests, such as nerve conduction studies in the lower limbs to confirm a sensory and motor<unk> . In sporadic cases, acquired<unk> es, such as the diabetic foot syndrome and alcoholic<unk> , can be excluded by the use of magnetic resonance imaging and by interdisciplinary discussion between neurologists, dermatologists, and orthopedics. The diagnosis of the disease has been revolutionized by the identification of the causative genes. The diagnosis is now based on the detection of the mutations by direct sequencing of the genes. Nevertheless, the accurate phenotyping of patients remains crucial in the diagnosis. For pregnant patients, termination of pregnancy is not recommended. HSAN I must be distinguished from hereditary motor and sensory<unk>  (HMSN) and other types of hereditary sensory and<unk> <unk> es (HSAN II-V). The prominent sensory abnormalities and foot ulcerations are the only signs to separate HSAN I from HMSN. HSAN II can be differentiated from HSAN I as it is inherited as an autosomal recessive trait, it has earlier disease onset, the sensory loss is diffused to the whole body, and it has less or no motor symptoms. HSAN III-V can be easily distinguished from HSAN I because of congenital disease onset. Moreover, these types exhibit typical features, such as the predominant<unk>  disturbances in HSAN III or congenital loss of pain and anhidrosis in HSAN IV. Subtypes In 1993, Peter James Dyck divided HSAN I further into five subtypes HSAN IA-E based on the presence of additional features. These features were thought to result from the genetic diversity of HSAN I (i.e. the expression of different genes, different alleles of a single gene, or modifying genes) or environmental factors. Molecular genetic studies later confirmed the genetic diversity of the disease. Subtype Gene or locus Mutation (DNA/Amino acid) Clinical features Age of onset OMIM IA SPTLC1 399T>G/C133W; 398G>A/C133Y; 431T>A/V144D Predominant loss of pain and temperature sensation; sometimes initial sign with long preservation of vibration sense; burning and lancinating pains; ulcerative mutilations; variable distal motor involvement Adolescence 162400 IB 3p24-p22 unknown Predominant sensory<unk>  with cough and gastroesophageal reflux; foot ulcerations (rare) Adulthood 608088 IC SPTLC2 1075G>A/V359M; 1145G>T/G382V; 1510A>T/I504F Loss of pain and temperature sensation; lancinating pain; ulcerative mutilations; variable distal motor involvement; acro-mutilating complications Adulthood 613640 ID ALT1 196G>C/E66Q; 976delG/V326WfsX8 Severe distal sensory loss and amyotrophy in lower limbs; trophic skin and nail changes; ulcerative mutilations Adulthood 613708 IE DNMT1 1484A>G/Y495C; 1470-1472TCC>ATA/D490E-P491Y Loss of all somatosensory modalities; lancinating pain; ulcerative mutilations; sensorineuronal hearing loss, dementia Adulthood 614116 : : : : : :
Hereditary sensory and autonomic neuropathy type I
Distal hereditary motor neuropathy type V
Familial amyloid neuropathy
Congenital myasthenic syndrome
Familial amyloid polyneuropathy
Hereditary motor and sensory neuropathy
Lambert–Eaton myasthenic syndrome
MGUS polyneuropathy