Form Of Hereditary Neuropathy Research Articles

Особливості клініко-лабораторної діагностики хвороби Помпе у дітей

Мета. Аналіз особливостей клінічної картини хвороби Помпе (ХП) у хворих дитячого віку. Визначення за результатами лабораторних та інструментальних досліджень основних клініко-лабораторних характеристик, що дозволяють виділити таких пацієнтів у групу селективного скринінгу для проведення ферментної діагностики на наявність ХП у сухій краплі крові. Матеріали та методи. В період 2002–2016 рр. у Центрі орфанних захворювань НДСЛ «Охматдит» обстежені 522 дитини з підозрою на ХП. Вік пацієнтів — від 4 місяців до 13 років; хлопчиків було 282, дівчаток — 240. Результати. У 98 (19 %) хворих за даними електронейроміографії і на підставі виявлення мутацій у гені SMN діагностована спінальна м’язова атрофія, у 70 (13 %) — первинна м’язова дистрофія Дюшена. У 71 (13,6 %) пацієнта виявлені різні форми спадкової нейромотосенсорної невропатії. У 38 (7,2 %) пацієнтів відзначали домінантний тип успадкування захворювання, в подальшому лабораторні дослідження з метою підтвердження діагнозу ХП у них не проводили. Отже, у селективну (скринінгову) групу для проведення ферментодіагностики у сухій краплі крові для виявлення ХП включено 245 (47 %) осіб. У цих пацієнтів відзначали гетерогенну клінічну картину захворювання: м’язову слабкість, зумовлену міопатичним синдромом, у поєднанні з кардіоміопатією, затримкою фізичного розвитку, гіперкреатинфосфатемією. У 25 хворих віком 2–8 місяців, крім міопатичного синдрому, спостерігали підвищення рівня аланінамінотрансферази та аспартатамінотрансферази, креатинфосфокінази (понад 220 од/л), лактатдегідрогенази (понад 250 од/л), гіпертрофічну кардіоміопатію лівого шлуночка; у 10 з цих хворих виявлені гепатомегалія та серцево-легенева недостатність. За результатами ферментодіагностики, діагноз ХП (інфантильна форма) встановлений у 5 пацієнтів (у 3 — класична форма, у 2 — атипова, або некласична). Клінічна картина була гетерогенною, проте в усіх спостереженнях відзначали сповільнене збільшення маси тіла, затримку формування статокінетичних навичок. Три пацієнти отримували ферментозамісну терапію, що дало можливість запобігти ранній смерті у цих пацієнтів і в одному випадку практично відновити самостійну ходьбу. Висновки. ХП у дітей характеризується мультисистемним ураженням, різними клінічними формами, за відсутності специфічного лікування призводить до ранньої смерті хворих. Основними ознаками ХП у дітей є гіпертрофічна кардіоміопатія, міопатичний синдром у поєднанні зі специфічним біохімічним фенотипом. Ферментодіагностика у сухій краплі крові в групі селективного скринінгу може підвищити ефективність ранньої діагностики та лікування дітей при ХП.

Prevalence and characterization of pain in patients with Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common form of hereditary neuropathy. To investigate the prevalence and characteristics of pain in patients with CMT1A. Nineteen patients with a diagnosis of CMT1A were evaluated between September 2018 and October 2019, and other causes of neuropathy were ruled out. The following tools were used for the pain assessment: neurological assessment, LANSS, DN4, clinical evaluation, VAS, CMTNS2 and SF-36. Statistical analysis was performed using prevalence analysis, t test, chi-square test and Spearman's rho. The prevalence of pain was 84.2% in the sample of this study, with moderate intensity and nociceptive characteristics according to the LANSS scale (75%) and clinical evaluation (50%), but differing from DN4, which found neuropathic pain in the majority of the patients (56.2%). Mixed pain was also observed in 43.7% of the patients, according to clinical criteria. There was a statistically significant correlation between pain intensity and SF-36, thus demonstrating that the lower the pain was, the lower the impairment was, in all domains. Pain is a prevalent and important symptom in CMT1A, with moderate intensity and nociceptive characteristics according to two tools, but neuropathic pain is also present, and there may even be a mixed pattern of pain. The correlation of the pain with SF-36 suggests that pain relief could provide improvements to the quality of life of these individuals.

The genetics of Charcot–Marie–Tooth disease: current trends and future implications for diagnosis and management

Charcot–Marie–Tooth (CMT) disease is the most common hereditary polyneuropathy and is classically associated with an insidious onset of distal predominant motor and sensory loss, muscle wasting, and pes cavus. Other forms of hereditary neuropathy, including sensory predominant or motor predominant forms, are sometimes included in the general classification of CMT, but for the purpose of this review, we will focus primarily on the forms associated with both sensory and motor deficits. CMT has a great deal of genetic heterogeneity, leading to diagnostic considerations that are still rapidly evolving for this disorder. Clinical features, inheritance pattern, gene mutation frequencies, and electrodiagnostic features all are helpful in formulating targeted testing algorithms in practical clinical settings, but these still have shortcomings. Next-generation sequencing (NGS), combined with multigene testing panels, is increasing the sensitivity and efficiency of genetic testing and is quickly overtaking targeted testing strategies. Currently, multigene panel testing and NGS can be considered first-line in many circumstances, although obtaining initial targeted testing for the PMP22 duplication in CMT patients with demyelinating conduction velocities is still a reasonable strategy. As technology improves and cost continues to fall, targeted testing will be completely replaced by multigene NGS panels that can detect the full spectrum of CMT mutations. Nevertheless, clinical acumen is still necessary given the variants of uncertain significance encountered with NGS. Despite the current limitations, the genetic diagnosis of CMT is critical for accurate prognostication, genetic counseling, and in the future, specific targeted therapies. Although whole exome and whole genome sequencing strategies have the power to further elucidate the genetics of CMT, continued technological advances are needed.

Role of stretch therapy in comprehensive physical habilitation of patients with Charcot–Marie–Tooth hereditary neuropathy

Charcot–Marie–Tooth hereditary neuropathy (Charcot–Marie–Tooth disease, CMT) is the most common form of hereditary neuropathies, accompanied by sensory disorders, progressive muscle weakness with the formation of disabling contractures of the limbs. Currently, the main treatment program is effective CMT habilitation, which can prevent the development of limb deformities and thereby improve the life quality of the patient. Stretch therapy is one of the most effective methods of prevention and treatment of contractures in patients with CMT. This article provides a brief review of the literature regarding the use of stretching as physical therapy program of CMT habilitation.

86. Unusual form of hereditary neuropathy with liability to pressure palsies

86. Unusual form of hereditary neuropathy with liability to pressure palsies

P0S63del impedes the arrival of wild-type P0 glycoprotein to myelin in CMT1B mice

More than 120 mutations in the Myelin Protein Zero gene (MPZ, P0) cause various forms of hereditary neuropathy. Two human mutations encoding either P0S63C or P0S63del have been shown to cause demyelination in mice through different gain of function pathomechanisms. P0S63del, for example, is retained in the endoplasmic reticulum (ER) and elicits a pathogenetic unfolded protein response (UPR). As P0 likely forms oligomers, another gain of abnormal function could include a dominant-negative interaction between P0S63del and normal P0 (P0wt). To test this idea, we generated a transgenic mouse that expressed a form of P0wt with a myc epitope tag at the C terminus (P0ct-myc). We show that P0ct-myc is trafficked and functions like P0wt, thus providing a new tool to study P0 in vivo. In mice that express both P0ct-myc and P0S63del, P0S63del specifically delays the transit of P0ct-myc through the ER and reduces the level of P0wt in the myelin sheath by half-a level previously shown to cause demyelination in mice and humans. Surprisingly, P0ct-myc does not co-immunoprecipitate with P0S63del, suggesting an indirect interaction. Thus, P0S63del causes not only a UPR-related toxic mechanism, but also a dominant-negative effect on P0wt that probably contributes to demyelinating neuropathy.

AUTOSOMAL RECESSIVE AND X-LINKED FORMS OF CHARCOT-MARIE-TOOTH DISEASE IN CHILDHOOD

Introduction: There are now more than 30 identified genes and 44 loci for the various forms of hereditary neuropathies. Hereditary sensory and motor neuropathy (HMSN; Charcot-Marie-Tooth disease;CMT) is commonly divided into demyelinating forms (including dominantly inherited subtypes – CMT1, and autosomal recessive forms – CMT4) and axonal neuropathies (CMT2), which can be inherited in both dominant (AD) and recessive (AR) fashion. A rarer X-linked form is designated CMTX.

Die Rolle des Immunsystems bei hereditären demyelinisierenden Neuropathien

Hereditary neuropathies, e.g., Charcot-Marie-Tooth (CMT) disease, are inherited diseases of the peripheral nervous system causing chronic progressive motor and sensory dysfunction. Most neuropathies are due to mutations in myelin genes such as PMP22, P0, and the gap junction protein Cx32. Myelin mutant mice are regarded as suitable animal models for several forms of hereditary neuropathies and are important neurobiological tools for the evaluation of pathogenetic and therapeutic concepts in hereditary neuropathies. Using these animal models we could recently show that the immune system is involved in the pathogenesis of hereditary neuropathies. Due to the phenotypic similarities we also consider the immune system important for human inherited neuropathies, in particular since several case reports demonstrate a beneficial effect of immune therapies in patients with hereditary neuropathies. In this review we compare findings from animal models and human disease to elucidate the role of the immune system in hereditary neuropathies.

Connexin mutations in X-linked Charcot-Marie-Tooth disease.

X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry technique, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a gap junction protein, suggest that connexin32 plays an important role in peripheral nerve.