A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated

Hereditary sensory neuropathy type 1 (HSAN I) is an autosomal dominant inherited neurodegenerative disorder of the peripheral nervous system associated with mutations in the SPTLC1 subunit of the serine palmitoyltransferase (SPT). Four missense mutations (C133W, C133Y, V144D and G387A) in SPTLC1 were reported to cause HSAN I. SPT catalyses the condensation of Serine and Palmitoyl-CoA, which is the first and rate-limiting step in the de novo synthesis of ceramides. Earlier studies showed that C133W and C133Y mutants have a reduced activity, whereas the impact of the V144D and G387A mutations on the human enzyme was not tested yet. In this paper, we show that none of the HSAN I mutations interferes with SPT complex formation. We demonstrate that also V144D has a reduced SPT activity, however to a lower extent than C133W and C133Y. In contrast, the G387A mutation showed no influence on SPT activity. Furthermore, the growth phenotype of LY-B cells—a SPTLC1 deficient CHO cell line—could be reversed by expressing either the wild-type SPTLC1 or the G387A mutant, but not the C133W mutant. This indicates that the G387A mutation is most likely not directly associated with HSAN I. These findings were genetically confirmed by the identification of a nuclear HSAN family which showed segregation of the G387A variant as a non-synonymous SNP.     

Late-onset hereditary sensory neuropathy type I due to SPTLC1 mutation: autopsy findings

There is little published information on the autopsy findings in hereditary sensory neuropathy type I (HSN I), and none in genetically confirmed cases. We report the neuropathological findings in a 93-year-old woman with a disease of unusually late onset, who was part of a large HSN I kindred and in whom genetic analysis confirmed an SPTLC1 T399G mutation.     

Novel NTRK1 mutations cause hereditary sensory and autonomic neuropathy type IV: demonstration of a founder mutation in the Turkish population

Hereditary sensory and autonomic neuropathy type IV (HSAN IV), or congenital insensitivity to pain with anhidrosis, is an autosomal recessive disorder characterized by insensitivity to noxious stimuli, anhidrosis from deinnervated sweat glands, and delayed mental and motor development. Mutations in the neurotrophic tyrosine kinase receptor type 1 (NTRK1), a receptor in the neurotrophin signaling pathway phosphorylated in response to nerve growth factor, are associated with this disorder. We identified six families from Northern Central Turkey with HSAN IV. We screened the NTRK1 gene for mutations in these families. Microsatellite and single nucleotide polymorphism (SNP) markers on the Affymetrix 250K chip platform were used to determine the haplotypes for three families harboring the same mutation. Screening for mutations in the NTRK1 gene demonstrated one novel frameshift mutation, two novel nonsense mutations, and three unrelated kindreds with the same splice-site mutation. Genotyping of the three families with the identical splice-site mutation revealed that they share the same haplotype. This report broadens the spectrum of mutations in NTRK1 that cause HSAN IV and demonstrates a founder mutation in the Turkish population. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Beyhan Tüysüz and Fatih Bayrakli contributed equally to this work.     

Expanding the spectrum of SPTLC1‐related disorders beyond hereditary sensory and autonomic neuropathies: A novel case of the distinct “S331 syndrome”

Hereditary sensory and autonomic neuropathies (HSAN) encompass a group of peripheral nervous system disorders characterized by remarkable heterogeneity from a clinical and genetic point of view. Mutations in SPTLC1 gene are responsible for HSAN type IA, which usually starts from the second to fourth decade with axonal neuropathy, sensory loss, painless distal ulcerations, and mild autonomic features, while motor involvement usually occur later as disease progresses. Beyond the classic presentation of HSAN type IA, an exceedingly rare distinct phenotype related to SPTLC1 mutations at residue serine 331 (S331) has recently been reported, characterized by earlier onset, prominent muscular atrophy, growth retardation, oculo‐skeletal abnormalities, and possible respiratory complications. In this report, we describe clinical, instrumental, and genetic aspects of a 13‐year‐old Sri Lankan male carrying the rare de novo p.S331Y heterozygous mutation in SPTLC1 gene found by whole exome sequencing. Patient's phenotype partly overlaps with the first case previously reported, however with some additional features not described before. This work represent the second report about this rare mutation and our findings strongly reinforce the hypothesis of a clearly distinct “S331 syndrome”, thus expanding the spectrum of SPTLC1‐related disorders.     

Hereditary sensory autonomic neuropathy type II: Report of two novel mutations in the FAM134B gene

Hereditary sensory autonomic neuropathy (HSAN) type II is a rare, autosomal recessive, and early onset sensory neuropathy, characterized by severe and progressive sensation impairment, leading to ulcero‐mutilating complications. FAM134B gene, also known as RETREG1 gene, mutations have been reported to be associated to HSAN‐IIB. We report four patients from two unrelated families who developed during childhood a sensory axonal neuropathy with variable severity and pronounced nociception impairment. Complications such as recurrent ulcerations, osteomyelitis, and osteonecrosis leading to distal amputation were noticed. Dysautonomia was mild or even absent in our group of patients. Additionally, either clinical or neurophysiological motor impairment was not uncommon. Presence of upper motor neuron signs was also a distinctive feature in two related patients. After extensive workup, two novel homozygous mutations in the FAM134B gene were identified. This report expands the clinical and genetic spectrum of HSAN type II and emphasizes the phenotype variability even within the same family.     

ATL3 gene mutation in a Chinese family with hereditary sensory neuropathy type 1F

Hereditary sensory neuropathy (HSN) comprises a group of progressive peripheral neuropathies predominantly affecting the sensory nerves. To date, two different ATL3 gene mutations have been reported to be responsible for HSN type 1F (HSN1F). Here, we report a family in which the members presented numbness of the lower limbs and recurrent foot ulceration. Symptoms of foot ulcers disappeared in the years after onset, which suggests that the family members showed benign and mild symptoms compared with the affected patients reported previously. Laboratory examinations and electrophysiological data suggested axonal degeneration of the peripheral sensory nerves, while motor neurons were not involved. Exome sequencing revealed the previously reported c.C1013G (p.Pro338Arg) mutation of the ATL3 gene. This is the first report of ATL3 mutation in Chinese patients with HSN. Cells expressing mutant ATL3 exhibited disruption of the endoplasmic reticulum network, suggesting a dominant‐negative effect. There was no significant difference in the expression of the endoplasmic reticulum stress marker binding immunoglobulin protein (BiP) between cells expressing wild‐type or mutant ATL3. Further studies are required to ascertain the relevance of the changes in endoplasmic reticulum morphology to axonal degeneration of sensory nerves.     

Hereditary sensory neuropathy type 1 in a Portuguese family-electrodiagnostic and autonomic nervous system studies

Hereditary sensory and autonomic neuropathy type 1 (HSAN 1) is a dominantly inherited disorder; its gene locus is mapped on chromosome 9q22. Three different missense mutations (C133Y, C133W and V144D) have been described in 11 families from Australia, England and Austria. Common clinical features have been found in these families. We report the clinical and electrophysiological features of three members of a large Portuguese family with HSAN 1 and the C133Y missense mutation. The affected members showed typical clinical features. Electrophysiological findings were consistent with a distal axonal predominantly sensory neuropathy with motor involvement, in three different severity stages. No autonomic involvement was detected in sudomotor and cardiovascular tests. This report documents the lesion of the motor nerve fibers in this disease, as well as the preservation of the autonomic nervous system function, therefore suggesting that HSNA is an inappropriate name for this disorder.     

Cerebral vasculopathy in a Chinese family with neurofibromatosis type I mutation

Neurofibromatosis type I (NF1) is a hereditary, autosomal dominant, neurocutaneous syndrome that is attributed to NF1 gene mutation. NF1 has been associated with scoliosis, macrocephaly, pseudoarthrosis, short stature, mental retardation, and malignancies. NF1-associated vasculopathy is an uncommon and easily-overlooked presentation. Examination of a Chinese family affected by NF1 combined with cerebral vessel stenosis and/or abnormality suggested a possible relationship between NF1 and vessel stenosis. To determine which NF1 gene mutation is associated with vascular lesions, particularly cerebral vessel stenosis, we examined one rare family with combined cerebral vessel lesions or maldevelopment. Vascular lesions were detected using transcranial Doppler sonography and digital subtraction angiography in family members. Next, denaturing high-performance liquid chromatography and sequencing were used to screen for NF1 gene mutations. The results revealed a nonsense mutation, c.541C>T, in the NF1 gene. This mutation truncated the NF1 protein by 2659 aminoacid residues at the C-terminus and co-segregated with all of the patients, but was not present in unaffected individuals in the family. Exceptionally, three novel mutations were identified in unaffected family members, but these did not affect the product of the NF1 gene. Thus the nonsense mutation, c.541C>T, located in the NF1 gene could constitute one genetic factor for cerebral vessel lesions.     

遗传性感觉交感神经病Ⅰ型一家系的临床、电生理和病理改变

目的报道一个遗传性感觉交感神经病Ⅰ型（HSANⅠ）家系的临床、病理和电生理改变特点。方法先证者为28岁男性，出现双下肢痛觉缺失1年余，伴随双脚多发溃疡，先证者之母在30岁出现双足麻木和溃疡。对先证者的周围神经和自主神经进行电生理检查，对腓肠神经进行病理检查。结果先证者手部皮肤交感反应延长，在足部没有引出；感觉神经传导速度在上肢出现减慢，（右尺神经33m／s，左正中神经45m／s），在下肢无反应；运动神经传导速度在上肢正常或减慢，在下肢减慢或无反应。腓肠神经的有髓神经纤维完全脱失，无髓神经纤维出现严重脱失。结论我国存在HSANⅠ型家系，病理检查显示有髓神经纤维和无髓神经纤维均被严重累及。皮肤交感反应检查交感神经损害的程度有助于该病的诊断。     

Novel mutation in the replication focus targeting sequence domain of DNMT1 causes hereditary sensory and autonomic neuropathy IE

DNMT1, encoding DNA methyltransferase 1 (Dnmt1), is a critical enzyme which is mainly responsible for conversion of unmethylated DNA into hemimethylated DNA. To date, two phenotypes produced by DNMT1 mutations have been reported, including hereditary sensory and autonomic neuropathy (HSAN) type IE with mutations in exon 20, and autosomal dominant cerebellar ataxia, deafness, and narcolepsy caused by mutations in exon 21. We report a sporadic case in a Japanese patient with loss of pain and vibration sense, chronic osteomyelitis, autonomic system dysfunctions, hearing loss, and mild dementia, but without definite cerebellar ataxia. Electrophysiological studies revealed absent sensory nerve action potential with nearly normal motor nerve conduction studies. Brain magnetic resonance imaging revealed mild diffuse cerebral and cerebellar atrophy. Using a next‐generation sequencing system, 16 candidate genes were analyzed and a novel missense mutation, c.1706A>G (p.His569Arg), was identified in exon 21 of DNMT1. Our findings suggest that mutation in exon 21 of DNMT1 may also produce a HSAN phenotype. Because all reported mutations of DNMT1 are concentrated in exons 20 and 21, which encode the replication focus targeting sequence (RFTS) domain of Dnmt1, the RFTS domain could be a mutation hot spot.     

A first Taiwanese Chinese family of type 2B von Willebrand disease with R1306W mutation

Clinical, laboratory and genetic defect of a Taiwanese family with type 2B von Willebrand disease (VWD) were studied. The proband was a 55-year-old woman who gave birth to two daughters and one son aged 30, 29 and 27, respectively. All had abnormal mucocutaneous bleedings since their childhood. In proband, PT, PTT and platelet count were normal; template bleeding time was 14 min; VIII:C was 51%, von Willebrand factor antigen (VWF:Ag), 42% and von Willerand factor ristocetin-cofactor (VWF:RCo, 15%); ristocetin-induced platelet aggregation (RIPA) at 0.3 and 0.6 mg/ml of ristocetin was 16% and 68%, respectively. The enhanced response to ristocetin was identified to be in plasma, not in platelet itself, by mixing studies. Analysis of von Willebrand factor (VWF) multimer of plasma but not of platelets showed absence of high-molecular weight (HMW) multimer. All three children had similar laboratory findings. Exon 28 of VWF gene was amplified using polymerase chain reaction (PCR) and sequenced. The proband and three children were all found to be heterozygous for C to T transition at nucleotide 3916 resulting in Arg 1306 Trp (R1306W) substitution. This mutation in the glycoprotein Ib (GPIb)-binding site has been found to increase the affinity of plasma VWF for platelets, and thus cause loss of HMW multimers and often thrombocytopenia. In conclusion, a first report of type 2B VWD in a Taiwanese Chinese family who show R1306W mutation in VWF gene was described.     

Hereditary sensory and autonomic neuropathy II due to novel mutation in the HSN2 gene in Mexican families

Journal of Neurology -     

Beyond neuropathy in hereditary sensory and autonomic neuropathy type V: cognitive evaluation

Background and purpose:  Hereditary sensory and autonomic neuropathy (HSAN) type V is a very rare disorder. It is characterized by the absence of thermal and mechanical pain perception caused by decreased number of small diameter neurons in peripheral nerves. Recent genetic studies have pointed out the aetiological role of nerve growth factor beta, which is also involved in the development of the autonomic nervous system and cholinergic pathways in the brain. HSAN type V is usually reported not to cause mental retardation or cognitive decline. However, a structured assessment of the cognitive profile of these patients has never been made.
Methods and results:  We performed a throughout evaluation of four HSAN type V patients and compared their performance with 37 normal individuals. Our patients showed no cognitive deficits, not even mild ones.
Discussion and Conclusions:  Although newer mutations on this and related disorders are continuously described, their clinical characterization has been restricted to the peripheral aspects of these conditions. A broader characterization of this rare disorder may contribute to better understand the mechanisms of the nociceptive and cognitive aspects of pain.     

A mutation in the HSN2 gene causes sensory neuropathy type II in a Lebanese family

Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder clinically characterized by distal and proximal sensory loss that is caused by the reduction or absence of peripheral sensory nerves. Recently, a novel gene called HSN2 has been found to be the cause of HSAN type II in five families from Newfoundland and Quebec. Screening of this gene in an HSAN type II Lebanese family showed a 1bp deletion mutation found in a homozygous state in all affected individuals. This novel mutation supports the hypothesis that HSN2 is the causative gene for HSAN type II.     

Hereditary motor and sensory neuropathy type I: Clinical and neurographical features of the 17p duplication subtype

Forty-four affected individuals, aged 8–68 years (mean 34 years), from six families with hereditary motor and sensory neuropathy type I (HMSN) I, Charcot–Marie–Tooth disease type (1) were investigated to determine the clinical and electroneurographical characteristics of the HMSN I subtype that is defined by the presence of a DNA duplication on chromosome 17p. Motor nerve conduction velocity (MNCV) and, to a lesser extent, compound muscle action potential amplitude, were inversely related to clinical severity. Neither clinical severity nor MNCV were significantly related to age. These results suggest that the primary pathological process is not, or only slightly active after childhood. © 1994 John Wiley & Sons, Inc.     

Hereditary motor and sensory neuropathy type 1 (HMSN1) associated with cranial neuropathy: an autopsy case report

A family with hereditary motor and sensory neuropathy type 1 (HMSN1) is reported. Three patients suffered only pupillary abnormality, two patients showed Adie's syndrome and peripheral neuropathy, and one had cranial neuropathy. Adie's syndrome and severe peripheral neuropathy. Autopsy of the latter revealed reduction of myelinated nerve fibers in the trigeminal, facial and hypoglossal nerves. There was extensive degeneration of the posterior column of the spinal cord. At the anterior horns, loss of motor neurons was observed, particularly at the lumbar level. The anterior and posterior roots showed loss of myelinated fibers. HMSN1 is only rarely associated with cranial neuropathy, and this is probably the first autopsy-proved case.     

Hereditary motor and sensory neuropathy with spastic paraplegia and optic atrophy: report on a family

We describe two siblings affected by a motor and sensory neuropathy starting in childhood. Already in infancy, a spastic gait disturbance had become obvious, leading later to multiple surgical interventions. In adolescence, progressive loss of vision developed. At the time of our examination, both siblings showed severe weakness and atrophy of the distal muscles of legs and arms. Tendon jerks were brisk in proximal muscles; in the lower extremities, muscle tone was increased. Visual acuity was severely decreased. Nerve conduction studies revealed an axonal degeneration. This finding was confirmed by evaluation of a sural biopsy specimen in one patient, showing only few remaining myelinated fibres without signs of demyelination. This combination of hereditary motor and sensory neuropathy with spastic paraplegia and optic atrophy shows features of both hereditary motor and sensory neuropathy V and VI according to the classification of Dyck, indicating that these subtypes may not represent distinct entities. Received: 24 February 1997 Received in revised form: 30 May 1997 Accepted: 26 July 1997     

Developments in autonomic research: a review of the latest literature

Small-diameter afferents do not just subserve pain and temperature sensibilities, important for protection of the body though they are: there is a system of low-threshold unmyelinated afferents that respond to light stroking (C-tactile afferents) and they are believed to subserve the affective components of touch. Patients with large-fibre sensory neuropathies exhibit skin sympathetic responses to stroking, and report the stimuli as feeling pleasant. Moreover, the posterior insula is activated. Patients with small-diameter sensory neuropathies, specifically those with congenital insensitivity to pain, suffer from cumulative injuries that can lead to joint degeneration. There is evidence that the nociceptive (and sympathetic) axons die because nerve growth factor is not being produced by the target tissues; patients with congenital insensitivity to pain have mutations in the NTRK1 gene, the gene responsible for producing the TrkA receptor, but there is also evidence for mutations in the SCN9A gene, which codes for a specific subunit of the voltage-gated sodium channel. Specific mutations, leading to clusters of cases of congenital insensitivity to pain, have been found in several geographical locations, with several genetic mutations having been documented. Interestingly, even patients with congenital insensitivity to pain, despite having never experienced pain, can still empathise with the pain in others—we do not need to feel pain in order to empathise, but we do need to feel pain in order to ensure that our body looks after itself.     

Phenotype and clinical course in a family with a new de novo Twinkle gene mutation

The Twinkle gene product is important for mtDNA replication. Only a few reports have investigated the clinically effect of mutations in this gene. We describe a new de novo mutation (1110C > A) in the PEO1 gene in a mother and her two sons. The mother had progressive ophthalmoplegia, limb weakness, sensory neuropathy, elevated resting plasma lactate, glucose intolerance and impaired VO_2max while her sons only had mild ptosis. In accordance with the clinical presentation, abnormal morphological findings in muscle and multiple deletions and depletion of mtDNA in muscle were more pronounced in the proband than in her sons.