[Progress in the diagnosis and treatment of Congenital insensitivity to pain with anhidrosis].

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disease which mainly affects infants, children and adolescents. As an autosomal recessive disorder, CIPA is also known as familial autonomic dysfunction type 2. The diagnosis of CIPA mainly relies on clinical observation and genetic testing. Currently there is lack of effective treatment, and it is mainly treated by cooling, anti-inflammatory and strengthened guardianization. This article has reviewed the literature and summarized the research on CIPA and progress made in its diagnosis and treatment, with an aim to improve the understanding of this disorder.

Cholinergic striatal neurons are increased in HSAN V homozygous mice despite reduced NGF bioavailability.

The neurotrophin Nerve growth factor (NGF) plays a critical role in the mature and developing nervous system. A point mutation (R100W) in the NGFB gene was found in patients with Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), which leads to pain insensitivity. In a previous work it has been shown that the mutation provokes a reduced secretion of mature NGF. In this study we generated and analyzed homozygous NGFR100W/R100W mice to understand whether the reduced NGF bioavailability can contribute to the clinical phenotype of the homozygous condition. We found that the majority of NGFR100W/R100W mice were born normal but failed to reach the first month of age. This early lethality was rescued by daily treatment with wild type NGF. In addition, we found that the density of cholinergic neurons of homozygous mice was unaffected in the medial septum and in the nucleus basalis of Meynert, whereas, suprisingly, it was increased specifically in the striatum. Due to the known action of the striatal cholinergic tone in modulating pain, our findings support the hypothesis that a central mechanism, linked to the NGFR100W-dependent increase of the striatal cholinergic tone, can contribute to the pain insensitivity observed in HSAN V patients.

A Case of Congenital Insensitivity to Pain With Anhidrosis Comorbid With Attention Deficit Hyperactivity Disorder: Clinical Implications for Pathophysiology and Treatment.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disorder caused by a mutation in the neurotrophic tyrosine kinase receptor (NTRK1) gene. CIPA is accompanied by abnormal catecholamine metabolism and decreased blood concentration of dopamine and norepinephrine. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder of heterogeneous etiology and presentation, and recent reports have suggested a pathophysiological role of neurotrophins in ADHD. Furthermore, dopamine and norepinephrine are known to play major roles in the pathophysiology of ADHD, and the imbalance of monoaminergic and cholinergic systems as an underlying cause of ADHD has recently been studied. Here, we report the case of an 11-year-old boy with CIPA and comorbid ADHD. Our observations have important clinical implications for patients with CIPA. Because of deficiencies in self-control, proper management of these patients necessitates a highly structured and monitored environment, made dually important by possible comorbidity of ADHD.

An Innovative Cooling Jacket to Combat Heat Intolerance in Children with Anhidrosis.

Hyperthermia and heat intolerance are distressing symptoms in patients with anhidrosis. Body cooling devices are an integral part of management of these patients. A cooling jacket made from easily available materials has been invented for a girl with congenital insensitivity to pain and anhidrosis with severe heat intolerance. This innovative cooling jacket may be helpful for anhidrotic children in resource-poor situations.

Hereditary motor and sensory neuropathies: Understanding molecular pathogenesis could lead to future treatment strategies.

Inherited peripheral neuropathies, like many other degenerative disorders, have been challenging to treat. At this point, there is little specific therapy for the inherited neuropathies other than genetic counseling as well as symptomatic treatment and rehabilitation. In the past, ascorbic acid, progesterone antagonists, and subcutaneous neurotrophin-3 (NT3) injections have demonstrated improvement in animal models of CMT 1A, the most common inherited neuropathy, but have failed to translate any effect in humans. Given the difficulty in treatment, it is important to understand the molecular pathogenesis of hereditary neuropathies in order to strategize potential future therapies. The hereditary neuropathies are in an era of molecular insight and over the past 20 years, more than 78 subtypes of Charcot Marie Tooth disease (CMT) have been identified and extensively studied to understand the biological pathways in greater detail. Next generation molecular sequencing has also improved the diagnosis as well as the understanding of CMT. A greater understanding of the molecular pathways will help pave the way to future therapeutics of CMT. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

Pediatric neuropathic arthropathy initially masquerading as inflammatory arthritis.

We describe a case of neuropathic arthropathy in the knees of a child eventually diagnosed with a hereditary sensory and autonomic neuropathy. The child was initially treated for rheumatologic disease at an outside institution. History and neurological workup revealed a neuropathy most consistent with hereditary sensory and autonomic neuropathy type II. Hereditary sensory and autonomic neuropathy should be considered in the differential diagnosis of children with joint abnormalities whose workup for an inflammatory arthropathy is negative and who exhibit diminished pain sensation on examination.

AAV-Mediated Gene Therapy for Glycosphingolipid Biosynthesis Deficiencies.

De novo glycosphingolipid (GSL) biosynthesis defects cause severe neurological diseases, including hereditary sensory and autonomic neuropathy type 1A (HSAN1A), GM3 synthase deficiency, and hereditary spastic paraplegia type 26 (HSPG26), each lacking effective treatment. Recombinant adeno-associated virus (AAV)-mediated gene therapy has emerged as a powerful treatment for monogenic diseases and might be particularly suitable for these neurological conditions.

Hereditary sensory autonomic neuropathy Type VIII: A rare clinical presentation, genomics, diagnosis, and management in an infant.

A 7-month-old female child born to nonconsanguineous parents with a history of global developmental delay, since early infancy had reported to the department with facial features of mild dysmorphism. History of finger sucking and finger biting was evident, as there was a massive scab tissue over the dorsal aspect of the index finger, above the finger nail bed. A huge ulcer was evident on the right side of the dorsal aspect of anterior two-thirds of the tongue. Genetic evaluation through targeted gene sequencing confirmed the diagnosis as hereditary sensory, autonomic neuropathy Type VIII (Online Mendelian Inheritance in Man - 616488). A homozygous missense variation in exon 3 of PRDM12 was detected. A multidisciplinary approach was planned for the management of the child. A soft splint on the maxilla was fabricated and stabilized with an adhesive. However, the final diagnosis was confirmed by a DNA genomic sequencing test, namely a multigene panel testing or comprehensive genomic sequencing.

Diagnosis and new treatments in genetic neuropathies.

The genetic neuropathies are a clinically and genetically heterogeneous group of diseases of which the most common types are Charcot-Marie-Tooth disease (CMT), the hereditary sensory and autonomic neuropathies and the distal hereditary motor neuropathies. More than 30 causative genes have been described, making an accurate genetic diagnosis increasingly possible. Although no specific therapies are yet available, research into their pathogenesis has revolutionised our understanding of the peripheral nervous system and allowed the development of rational approaches to therapy. The first therapeutic trials in CMT are currently underway. This review will suggest an approach to the diagnosis of these disorders and provide an update on new therapies.

Spinal anesthesia in a patient with congenital insensitivity to pain with anhidrosis.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare, hereditary, autonomic recessive disorder. The inability to perceive pain results from loss of nociceptive afferents, while anhidrosis is caused by loss of innervation to the sweat glands. Insensitivity to pain and mental retardation lead to self-inflicted injuries, corneal lacerations, painless bony fractures, joint deformities with consequent chronic osteomyelitis, and septic arthritis. There are only a few reports on the anesthetic management for patients with CIPA. We describe the anesthetic management of a young woman with CIPA receiving bilateral arthrodesis of the ankle.

Orthopaedic manifestations of congenital indifference to pain with anhidrosis (Hereditary Sensory and Autonomic Neuropathy type IV).

BACKGROUND: Congenital indifference to pain with anhidrosis (CIPA) is a rare hereditary neuropathy, which is associated with defective sensation to noxious stimuli and autonomic dysfunction. The objective of the study was to report on the orthopaedic manifestations of this condition and provide an evidence-based approach for management. METHODS: Retrospective review of 14 consecutive patients with CIPA referred to a single tertiary centre. Mean age of diagnosis was 2.5 years (range 0.5 to 11 years). RESULTS: Patients presented with a range of orthopaedic problems including fractures, infections, growth disturbance, joint subluxation and Charcot joints affecting the limbs and spine. Conservative treatment with closed reduction and cast immobilisation was satisfactory for stress fractures of the lower extremity and Charcot joints. Posterior instrumented correction of scoliosis was associated with a high-risk of infection requiring reoperation for debridement and removal of posterior instrumentation. Growth disturbance leading to leg-length discrepancies were managed with shoe raises and corrective osteotomies. Aspiration and cultures may be used to differentiate between acute fracture and infection. CONCLUSIONS: Preventative treatment strategies with appropriately padded shoe-wear, gait and posture modification, parental education regarding environmental thermoregulation, and behavioural support are essential for improving prognosis and reducing long-term complications.

Congenital insensitivity to pain with anhidrosis: A report of two siblings with a novel mutation in (TrkA) NTRK1 gene in a Saudi family.

Congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN type IV) is an extremely rare autosomal recessive disorder with an estimated incidence of 1 in 25,000. It was first described in 1963, and since then several case reports and review articles have been published. In this article, we report two brothers with clinical features of CIPA, who presented with recurrent episodes of hyperthermia, anhidrosis, profound loss of pain sensitivity, and unconscious self-mutilation of fingers, lip and tongue. Sanger sequencing analysis confirmed the presence of a novel mutation c.783_785delGAA in the NTRK1 gene in the two affected members of the family. Early diagnosis and management of different systemic complications including orthopedic, visual, and dental may be useful in the reduction of frequency and severity of these complications.

Molecular pathogenesis, experimental therapy and genetic counseling in hereditary sensory neuropathies.

Hereditary sensory and autonomic neuropathies (HSANs) represent a group of heritable peripheral nerve disorders usually taking a severe clinical course. HSAN-affected patients manifest with deep, poorly-healing ulcerations of the feet and hands. To date no definitive cure for HSANs has been developed and the molecular pathology of these disorders is complex. The aim of this review is therefore to present recent findings in terms of HSAN molecular pathogenesis. So far, mutations in 12 genes coding for different proteins have been reported in association with HSAN and the molecular pathogenesis has been elucidated in HSAN1a, HSAN4 and HSAN5. The genes involved in molecular pathogenesis of HSAN code for a wide spectrum of proteins from enzymes to specific nerve growth factors. As far as HSAN1a is concerned, the enhanced understanding has given rise to achievements in experimental therapy particularly in respect to disease models. Despite a rapid progress in studies on the molecular background of HSAN, numerous loci and genes remain still to be discovered.

Motor neuropathies mimicking amyotrophic lateral sclerosis/motor neuron disease.

We report three patients in whom the initial diagnosis was of possible A myotrophic lateral sclerosis (ALS/MND) according to the 'El Escorial Criteria'. All of them presented with monomelic paresis, atrophy of the paretic muscles and generalised brisk reflexes. The initial electromyograms showed a neurogenic pattern in the limbs with normal sensory and motor conduction velocities. Laboratory evaluation and imagiological investigations were normal in all of them. The previous diagnosis was changed in to demyelinating motor neuropathy with conduction block in 2 patients and tomaculous neuropathy in one after clinical and electromyographic follow-up and nerve biopsy. Patients 1 and 2 were given intravenous immunoglobulin treatment and showed moderate improvement.

The sick sinus syndrome in familial amyloidosis with polyneuropathy.

We report five cases of dysfunction of the sinus node in patients suffering from familial amyloidosis with polyneuropathy. The implantation of a pacemaker resulted in symptomatologic relief in all.

A case of a hereditary, late progressing sensory autonomic neuropathy.

A case of a hereditary sensory autonomic neuropathy (HSAN) with severe medical complications that had been reported as nonprogressive HSAN type II has been followed and treated for a period of 10 years, and is now considered to be progressive HSAN type III, is presented. Current difficulties in the present form of the classification of HSAN, the necessity to observe these cases for longer periods and possible prolongation of survival with appropriate supportive treatment are emphasized.

Autonomic neuropathy: clinical presentation and differential diagnosis.

Autonomic neuropathy (AN) may occur in the elderly in connection with other common illnesses afflicting this age group, such as diabetes or Parkinson's disease, or even as the primary illness. Symptoms of AN are numerous, but syncope, with its risk for fractures and head trauma, is the most serious. The clinical presentation and differential diagnosis of AN are discussed, as are a group of diseases associated with AN. Treatment guidelines are outlined.