Hereditary sensory neuropathy type I (HSN I)

Hereditary sensory and autonomic neuropathy type I (HSAN I)

Charcot-Marie Tooth type 2B syndrome (HMSN 2B)

Hereditary sensory radicular neuropathy*

Ulcero-mutilating neuropathy*

Thevenard syndrome*

Familial trophoneurosis*

Mal perforant du pied*

Familial syringomyelia*

Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset.

Hereditary sensory neuropathy type I (HSN I) constitutes a clinically and genetically heterogenous group of disorders of low prevalence. No detailed epidemiological data are currently available. The disease frequency is still reflected by reports of several affected families. Although the impressive clinical features of HSN I are seen by neurologists, general practitioners, orthopaedists and dermatologists, the condition might still be under-recognised. This is particularly true for cases without family history and those HSN I patients who do not exhibit the characteristic clinical features.

Hereditary sensory neuropathies (HSN), also known as hereditary sensory and autonomic neuropathies (HSAN), belong to the large group of hereditary neuropathies. Typically, the HSNs predominantly affect peripheral sensory and autonomic neurons but there is also variable motor involvement 1. The classification of the HSNs proposed by Dyck et al was suggested before the detection of responsible genes and was thus based on the age at onset, the mode of inheritance and the predominant phenotype. It comprises five main subtypes (HSN, HSAN types 1–5). HSN (HSAN) type I (HSN I) is characterised by autosomal dominant inheritance and juvenile or adulthood disease onset. The congenital and early onset forms of HSN are subcategorised as subtypes HSN II – V and are transmitted by an autosomal recessive trait 1.

This review focuses on HSN type I. Molecular genetic studies in the past years have demonstrated genetic heterogeneity between the HSN I subtypes. The summary provided in the next paragraph describes clinical and neurological abnormalities in which the diagnosis HSN I should be considered in a patient or a family.

A main and consistent feature of HSN I is the reduction of sensation sense which is mainly distributed to the distal parts of the upper and lower limbs (Table 1). Disease onset varies between the 2^nd and 5^th decade of life. At the beginning patients often notice distal sensory loss and/or slow healing of wounds and/or chronic skin ulcers. The latter changes appear due to permanent pressure, i.e. long walks or when patients wear shoes that do not fit well. Minimal wounds or blisters may then lead to deep foot ulcerations. Other patients first recognise that they cannot distinguish warm and cold stimuli, and that they are insensitive to pain. When they get painless burns and injuries they seek medical advice 1. Neurological examination detects distal sensory disturbances, which may affect all sensory qualities or selectively affect pain and temperature sensation with preservation of vibration and joint position sense. This dissociated sensory involvement is typically seen in patiens with SPTLC1 mutations and occurs in early stages of the disease 2. The degree of motor involvement is highly variable, even within families, and ranges from absent to severe distal muscle weakness and wasting of foot extensors leading to steppage gait. In patients with marked involvement of the motor nerves, the additional presence of prominent sensory abnormalities and foot ulcerations are the only signs to separate HSN I from hereditary motor and sensory neuropathy (HMSN, i.e. Charcot-Marie-Tooth syndrome, CMT) 34. Foot deformity promotes ulcerations and skin changes such as hyperkeratosis at pressure points, which is also often prominent in HSN I. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, and neuropathic arthropathy which may even necessitate amputations. Also autonomic features are often observed and usually consist of sweating disturbances. With progression of the disease, loss of sensation and motor weakness may spread from distal parts of the lower limbs to more proximal parts, but also the hands may become similarly involved. In some reported HSN I families, hypacusis or deafness, or cough and gastrooesophageal reflux have been observed. Some patients experience positive symptoms of severe shooting, burning and lancinating pain in the limbs or even in the trunk 1. These symptoms are more frequently described in patients with SPLTC1 mutations 2. The disorder is slowly progressive, but is often severely disabling after a long duration of the disease 125.

In HSN I there is broad variability of electrophysiological abnormalities within and between families. Primarily axonal nerve damage of both motor and sensory nerves has been shown. Sensory potentials are usually absent in the lower limbs but are often recordable or even normal in the upper limbs, particularly in females 16. The study of Whitaker et al in the family later shown to carry a SPTLC1 mutation and the study by Dubourg et al also show motor conduction slowing, possibly implying a demyelinating process 78. Neurophysiological studies in CMT2B patients with a RAB7 mutation showed a mixed motor and sensory neuropathy with axonal and sometimes also demyelinating nerve damage 29. Sural nerve biopsy findings were well studied in six English patients with a SPTLC1 mutation. In severely affected nerves only a very few myelinated fibres remained but electron microscopy showed a reasonable number of unmyelinated axons although the presence of stacks of flattened Schwann cell processes suggested unmyelinated axon loss. There was also some evidence for primary demyelination 6.

HSN I is a genetically heterogenous condition. In the past two decades the introduction of genome-wide linkage studies enabled genetic testing of several HSN families and resulted in the elucidation of the molecular genetic background of these diseases. Detailed family studies clearly demonstrated clinical and genetic heterogeneity of HSN I and three gene loci and two genes were subsequently identified 10. Table 2 summarises the known genes and gene loci and the phenotypic characteristics of the HSN I subtypes. A clinician should always be aware that the diagnosis of HSN I depends on patients having severe sensory loss sufficient to cause painless injuries or ulcerations. A comprehensive family history may also often serve to a correct diagnosis.

A subdivision into HSN IA, HSN IB, HSN IC, and HSN ID which is based on the different genetic background is proposed here.

In a single patient, the clinical diagnosis of HSN I is based on the observation of signs and symptoms described above, and is supported by a family history suggesting autosomal dominant inheritance. The diagnosis is supported by ancillary tests such as nerve conduction studies which are needed to confirm a sensory and motor neuropathy predominantly affecting the lower limbs. In sporadic cases acquired neuropathies have to be excluded (see differential diagnosis) by use of several laboratory tests. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. With the discovery of several distinct HSN loci, and ultimately the deciphering of the underlying gene defects, the definitive diagnosis is now molecular and is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Large families in which mutations in SPTLC1 and RAB7 are excluded can be used for genome wide linkage studies to detect a novel HSN I locus or to confirm linkage to the third known HSN I locus (i.e. the HSN IB locus). Such large HSN families will be most helpful to identify further genes which are involved in the pathogenesis of HSN I.

HSN I must be distinguished from other forms of hereditary sensory neuropathies (HSN types II-V). The phenotype of HSN II is often similar to that of HSN I. The main differences are the autosomal recessive pattern of inheritance of HSN II, an earlier disease onset, diffuse sensory loss which is sometimes distributed to the whole body, and less or no motor symptoms in HSN II. HSN II patients also often exhibit early-onset of severe acro-mutilations in the fingers. HSN III to HSN V can be easily distinguished from HSN I because of congenital disease onset. Also, these subtypes exhibit typical features such as the predominant autonomic disturbances in HSN III or congenital loss of pain and anhidrosis in HSN IV.

Particularly in sporadic patients with an HSN I phenotype it is important to exclude acquired causes of ulcero-mutilating neuropathies. The major differential diagnoses are the diabetic foot syndrome and alcoholic neuropathy. Exclusion of other causes of neuropathies can usually be done by laboratory and radiological studies, and requires interdisciplinary discussion between neurologists, dermatologists, and orthopaedics. Table 3 summarises other diseases which may mimick HSN I or are associated with plantar foot ulcers.

As the disorder is inherited by an autosomal dominant trait, previous family history is often reported. There is thus a Mendelian risk of 50% for subsequent generations independently from the sex of the affected individual and the child. Genetic counselling is an important tool for preventing new cases if this is wished by at-risk family members. Predictive testing of mutation carriers necessitates accurate genetic counselling but is certainly useful for young people to avoid serious complications of the disease.

Molecular genetic diagnosis can be considered in families where the disease causing mutation is known. However, termination of pregnancy is not recommened in HSN1. When a patient is male, artificial insemination with donor sperm is another option that could be discussed with the couple during genetic counselling.

No gene-based therapies are available to date for any variant of autosomal dominant HSN. Yet, accurate diagnosis is important and is requested by patients and at-risk family members. Ulcero-mutilating complications are the most serious, prominent and leading diagnostic feature in HSN I. The painless neuropathic foot ulcerations observed in several subtypes of autosomal dominant HSN often mimic foot ulcers caused by diabetic neuropathy and thus resemble a "pseudodiabetic foot syndrome". Therefore, treatment of foot ulcers and infections can follow the guidelines given for diabetic foot care which starts with early and accurate counselling of patients about risk factors for developing foot ulcerations. This of course includes orthopaedic care and use of well fitting shoes without pressure points. To date, treatment of foot complications has reached an efficient level allowing treatment on an outpatient basis. Early treatment of foot complications often avoids hospitalisation and, in particular, complications like amputations. Principles of therapy are removal of pressure to the ulcer, eradication of infection and specific protective footwear afterwards.

If patients with HSN I receive appropriate counselling and treatment, the prognosis is good. Early treatment of foot infections may avoid serious complications. Also the complications are manageable, allowing an acceptable quality of life. The disease is slowly progressive and does not influence the life expectancy.

It is still unclear how mutations in the SPTLC1 and RAB7 genes lead to the phenotype of HSN I. For many families and single HSN cases the genetic background still remains unknown due to the genetic heterogeneity of the autosomal dominant HSN. There is still no causative treatment of HSN. Pharmacological treatment or gene therapy are needed but require a better understanding of the molecular and functional mechanisms underlying the different genetic subtypes of HSN I.