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GeneReviews® [Internet], 2020
Revue : GeneReviews® [Internet] Titre : Hereditary Neuropathy with Liability to Pressure Palsies : Synonym: HNPP Type de document : Article Auteurs : Chrestian N Année de publication : 27/08/2020 Langues : Anglais (eng) Mots-clés : article de synthèse ; conseil génétique ; corrélation génotype-phénotype ; description de la maladie ; diagnostic ; diagnostic différentiel ; épidémiologie ; physiopathologie ; prévalence ; prise en charge thérapeutique Résumé : Initial Posting: September 28, 1998; Last Update: August 27, 2020.
Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent acute sensory and motor neuropathy in a single or multiple nerves. The most common initial manifestation is the acute onset of a non-painful focal sensory and motor neuropathy in a single nerve (mononeuropathy). The first attack usually occurs in the second or third decade but earlier onset is possible. Neuropathic pain is increasingly recognized as a common manifestation. Recovery from acute neuropathy is usually complete; when recovery is not complete, the resulting disability is mild. Some affected individuals also demonstrate a mild-to-moderate peripheral neuropathy.
The diagnosis of HNPP is established in a proband with suggestive clinical and electrophysiologic findings and either the 1.5-Mb recurrent deletion or a novel deletion involving PMP22 (in 80%), or a PMP22 sequence variant (in 20%) identified by molecular genetic testing.
Treatment of manifestations: Treatment is symptomatic and involves occupational therapy and physical therapy as needed to address issues with fine motor and gross motor skills, including activities of daily living. Bracing, such as with a wrist splint or ankle-foot orthosis, may be useful transiently or in some instances permanently. Special shoes, including those with good ankle support, may be needed. Neuropathic pain can be treated with analgesic medications. Protective pads at elbows or knees may prevent pressure and trauma to local nerves.
Surveillance: Routine screening neurologic examination focused on muscle atrophy, strength, sensory loss, and neuropathic pain; physical and occupational therapy assessments of gross motor and fine motor skills and activities of daily living; foot examinations for pressure sores or poorly fitting footwear.
Agents/circumstances to avoid: Prolonged sitting with legs crossed; prolonged leaning on elbows; occupations requiring repetitive movements of the wrist; rapid weight loss; vincristine.
Evaluation of relatives at risk: Asymptomatic relatives at risk may wish to clarify their genetic status by undergoing molecular genetic testing for the PMP22 pathogenic variant identified in an affected family member in order to be advised about agents and circumstances to avoid.
HNPP is inherited in an autosomal dominant manner. Approximately 20% of individuals with HNPP have the disorder as the result of a de novo PMP22 pathogenic variant. Each child of an affected individual is at a 50% risk of inheriting the PMP22 pathogenic variant. Once the PMP22 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Lien associé : Texte complet disponible en accès libre sur Bookshelf GeneReviews® Pubmed / DOI : Pubmed : 20301566Ferreira C, Pierre G, Thompson R, et al.
GeneReviews® [Internet], 2020
Revue : GeneReviews® [Internet] Titre : Barth Syndrome Type de document : Article Auteurs : Ferreira C ; Pierre G ; Thompson R ; Vernon H Année de publication : 09/07/2020 Langues : Anglais (eng) Mots-clés : article de synthèse ; conseil génétique ; corrélation génotype-phénotype ; description de la maladie ; diagnostic ; diagnostic différentiel ; diagnostic moléculaire ; épidémiologie ; physiopathologie ; prévalence ; prise en charge thérapeutique ; syndrome de Barth Résumé : nitial Posting: October 9, 2014; Last Update: July 9, 2020.
Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies.
The diagnosis of Barth syndrome is established in a male proband with either an increased monolysocardiolipin:cardiolipin ratio (if available) or a hemizygous pathogenic variant in TAZ identified by molecular genetic testing. The diagnosis of Barth syndrome is usually established in a female proband with suggestive clinical findings and a TAZ pathogenic variant identified by molecular genetic testing.
Treatment of manifestations: Standard treatment of heart failure including careful fluid and volume management and avoidance of over-diuresis and dehydration, standard heart failure medications to improve symptoms, and cardiac transplantation when heart failure is severe and intractable; consideration of antiarrhythmic medications or implantable cardiac defibrillator for cardiac arrhythmia; granulocyte colony-stimulating factor for neutropenia; physical therapy for skeletal muscle weakness; standard treatment for talipes equinovarus and/or scoliosis; feeding therapy and consideration of gastrostomy tube for persistent feeding issues; uncooked cornstarch prior to bedtime for hypoglycemia; standard treatment for developmental delay / intellectual disability.
Prevention of secondary complications: Aspirin therapy for prevention of clot formation in those with severe cardiac dysfunction and/or marked left ventricular noncompaction; antibiotic prophylaxis to prevent recurrent infections; limiting fasting or providing intravenous glucose infusion prior to planned procedures; regular monitoring of potassium levels during administration of IV fluids that contain potassium and during episodes of diarrhea; consultation with a nutritionist and/or gastroenterologist to determine optimal caloric delivery.
Surveillance: At least annual electrocardiography with Holter monitor and echocardiography; electrophysiologic study to assess for potentially serious arrhythmia as needed; complete blood count with differential with all febrile episodes and at least semiannually; measurement of height and weight, clinical assessment of strength and for scoliosis, and assessment of developmental progress and educational needs at each visit; formal developmental assessments every three to five years during childhood.
Agents/circumstances to avoid: Prolonged fasting, use of rectal thermometers in those with neutropenia, and use of succinylcholine. Growth hormone is typically discouraged unless growth hormone deficiency is conclusively established, as the majority of affected males will attain normal stature by adulthood. The muscular involvement in Barth syndrome may increase the risk for malignant hyperthermia compared to the general population.
Evaluations of relatives at risk: It is appropriate to evaluate the older and younger brothers of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.
Pregnancy management: Pregnancies of male fetuses known to have Barth syndrome should be managed by a high-risk maternal fetal obstetrician; there are no specific recommendations regarding mode, timing, or location of delivery.
Barth syndrome is inherited in an X-linked manner. If a mother has a TAZ pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the TAZ pathogenic variant will be affected; females who inherit the TAZ pathogenic variant are typically not affected. Affected males pass the TAZ pathogenic variant to all of their daughters and none of their sons. Testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the TAZ pathogenic variant has been identified in an affected family member.
Lien associé : Texte complet disponible en accès libre sur Bookshelf GeneReviews® Pubmed / DOI : Pubmed : 25299040
Multiple Acyl-CoA Dehydrogenase Deficiency : Synonyms: Electron Transfer Flavoprotein Dehydrogenase Deficiency, Glutaric Acidemia II, Glutaric Aciduria II, MADDPrasun P
GeneReviews® [Internet], 2020
Revue : GeneReviews® [Internet] Titre : Multiple Acyl-CoA Dehydrogenase Deficiency : Synonyms: Electron Transfer Flavoprotein Dehydrogenase Deficiency, Glutaric Acidemia II, Glutaric Aciduria II, MADD Type de document : Article Auteurs : Prasun P Année de publication : 18/06/2020 Langues : Anglais (eng) Mots-clés : acyl-CoA déshydrogénase (maladie neuromusculaire liée à) ; article de synthèse ; conseil génétique ; corrélation génotype-phénotype ; description de la maladie ; diagnostic ; diagnostic différentiel ; épidémiologie ; incidence ; lipidose ; myopathie métabolique héréditaire ; physiopathologie ; prise en charge thérapeutique Résumé : Clinical characteristics.
Multiple acyl-CoA dehydrogenase deficiency (MADD) represents a clinical spectrum in which presentations can be divided into type I (neonatal onset with congenital anomalies), type II (neonatal onset without congenital anomalies), and type III (late onset).
Individuals with type I or II MADD typically become symptomatic in the neonatal period with severe metabolic acidosis, which may be accompanied by profound hypoglycemia and hyperammonemia. Many affected individuals die in the newborn period despite metabolic treatment. In those who survive the neonatal period, recurrent metabolic decompensation resembling Reye syndrome and the development of hypertrophic cardiomyopathy can occur. Congenital anomalies may include dysmorphic facial features, large cystic kidneys, hypospadias and chordee in males, and neuronal migration defects (heterotopias) on brain MRI.
Individuals with type III MADD, the most common presentation, can present from infancy to adulthood. The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain, although metabolic decompensation with episodes of rhabdomyolysis can also be seen. Rarely, individuals with late-onset MADD (type III) may develop severe sensory neuropathy in addition to proximal myopathy.
The diagnosis of MADD is established in a proband with elevation of several acylcarnitine species in blood in combination with increased excretion of multiple organic acids in urine and/or by identification of biallelic pathogenic variants in ETFA, ETFB, or ETFDH.
Treatment of manifestations: Routine daily treatment includes limitation of protein and fat in the diet, avoidance of prolonged fasting, high-dose riboflavin (100-300 mg daily), carnitine supplementation (50-100 mg/kg daily in 3 divided doses) in those with carnitine deficiency, and coenzyme Q10 supplements (60-240 mg daily in 2 divided doses). Further treatments include feeding therapy with consideration of gastrostomy tube for those with failure to thrive, as well as standard treatment for developmental delay, cardiac dysfunction, and sensory neuropathy. Emergency outpatient treatment for mild decompensation includes decreasing the fasting interval, administration of antipyretics for fever, and antiemetics for vomiting. Acute treatment includes hospitalization with intravenous fluid containing at least 10% dextrose, and bicarbonate therapy depending on the metabolic status.
Prevention of primary manifestations: Avoidance of fasting and supplementation with riboflavin, L-carnitine, and coenzyme Q10; a diet restricted in fat and protein is prescribed for some affected individuals based on the severity of the disorder.
Prevention of secondary complications: Education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors. Prompt initiation of dextrose containing intravenous fluids is essential to avoid complications such as liver failure, rhabdomyolysis, encephalopathy, and coma. Written protocols for emergency treatment should be provided to parents and primary care providers/pediatricians, and to teachers and school staff.
Surveillance: Measurement of plasma free and total carnitine, acylcarnitine profile, serum creatine kinase (CK), urine organic acids, head circumference (in infants and children), and growth and developmental milestones at each visit; neuropsychological testing and standardized quality-of-life assessment tools for affected individuals and parents/caregivers as needed; EKG and echocardiogram annually for individuals with severe forms of MADD and less frequently for individuals with milder presentations.
Agents/circumstances to avoid: Inadequate caloric provision during stressors (including following vaccination); prolonged fasting; dehydration; high-fat, high-protein diet; volatile anesthetics and those that contain high doses of long-chain fatty acids; administration of intravenous intralipids during an acute metabolic crisis.
Evaluation of relatives at risk: Testing of all at-risk sibs of any age is warranted (targeted molecular genetic testing if the familial pathogenic variants are known in parallel with plasma acylcarnitine profile, plasma free and total carnitine, and urine organic acid assay) to allow for early diagnosis and treatment of MADD.
Pregnancy management: Successful pregnancy with low-fat, high-carbohydrate diet in late-onset MADD has been published. There is no evidence to suggest that taking supplemental carnitine during pregnancy leads to adverse fetal effects. Riboflavin is a B vitamin and is considered an essential nutrient that is likely eliminated through feces and urine and does not result in excessive tissue absorption.
MADD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% change of being affected, a 50% chance of being unaffected and a carrier, and a 25% change of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.
Lien associé : Texte complet disponible en accès libre sur Bookshelf GeneReviews® Pubmed / DOI : Pubmed : 32550677
MFN2 Hereditary Motor and Sensory Neuropathy : Synonyms: MFN2 Charcot-Marie-Tooth Neuropathy, MFN2-HMSNZüchner S
GeneReviews® [Internet], 2020
Revue : GeneReviews® [Internet] Titre : MFN2 Hereditary Motor and Sensory Neuropathy : Synonyms: MFN2 Charcot-Marie-Tooth Neuropathy, MFN2-HMSN Type de document : Article Auteurs : Züchner S Année de publication : 14/05/2020 Langues : Anglais (eng) Mots-clés : article de synthèse ; conseil génétique ; corrélation génotype-phénotype ; description de la maladie ; diagnostic ; diagnostic différentiel ; épidémiologie ; étiologie ; gène MFN2 ; génétique moléculaire ; maladie de Charcot-Marie-Tooth ; maladie du système nerveux périphérique ; nosologie ; physiopathologie ; prévalence ; prise en charge thérapeutique Résumé : Initial Posting: February 18, 2005; Last Update: May 14, 2020.
MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is a classic axonal peripheral sensorimotor neuropathy, inherited in either an autosomal dominant (AD) manner (~90%) or an autosomal recessive (AR) manner (~10%). MFN2-HMSN is characterized by more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, more prominent motor deficits than sensory deficits, and normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs). Postural tremor is common. Median onset is age 12 years in the AD form and age eight years in the AR form. The prevalence of optic atrophy is approximately 7% in the AD form and approximately 20% in the AR form.
Molecular genetic testing establishes the diagnosis of MFN2-HMSN in 90% of probands with suggestive findings by identifying a heterozygous MFN2 pathogenic variant and in 10% of probands with suggestive findings by identifying biallelic MFN2 pathogenic variants.
Treatment of manifestations: Neuropathy is often managed by a multidisciplinary team that includes a neurologist, a physiatrist, an orthopedic surgeon, and physical and occupational therapists. Symptomatic treatment relies on special shoes and/or ankle/foot orthoses to correct foot drop and aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility; exercise as tolerated; acetaminophen or nonsteroidal anti-inflammatory agents for musculoskeletal pain; treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin. Optic atrophy is managed with low vision aids as per a low vision clinic, consultation with community vision services, and career/employment counseling.
Surveillance: Routine evaluation by: a neurologist to assess disease progression; physical therapy to assess gross motor skills including gait and strength; occupational therapy to assess fine motor skills and coping strategies; and ophthalmologist and low vision clinic to assess visual acuity and need for modification of low vision aids, respectively.
Agents/circumstances to avoid: Obesity (which makes ambulation more difficult); medications (e.g., vincristine, isoniazid, nitrofurantoin) known to cause nerve damage; alcohol and malnutrition (which can cause or exacerbate neuropathy).
Approximately 90% of MFN2-HMSN is inherited an autosomal dominant (AD) manner, and approximately 10% is inherited in an autosomal recessive (AR) manner. Semi-dominant inheritance (i.e., an MFN2 pathogenic variant is associated with mild disease in the heterozygous state and more severe disease in the homozygous or compound heterozygous state) has been reported in two families.
AD MFN2-HMSN. Most affected individuals have an affected parent; the proportion of individuals with a de novo MFN2 pathogenic variant is unknown. Each child of an affected individual has a 50% chance of inheriting the MFN2 pathogenic variant.
AR MFN2-HMSN. At conception, each sib of an individual with autosomal recessive MFN2-HMSN has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote (i.e., carrier), and a 25% chance of being unaffected and not a carrier.
Once the MFN2 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MFN2-HMSN are possible.
Lien associé : Texte complet disponible en accès libre sur Bookshelf GeneReviews® Pubmed / DOI : Pubmed : 20301684Preston MK, Tawil R, Wang LH
GeneReviews® [Internet], 2020
Revue : GeneReviews® [Internet] Titre : Facioscapulohumeral Muscular Dystrophy : Synonym: FSH Muscular Dystrophy Type de document : Article Auteurs : Preston MK ; Tawil R ; Wang LH Année de publication : 06/02/2020 Langues : Anglais (eng) Mots-clés : article de synthèse ; conseil génétique ; corrélation génotype-phénotype ; diagnostic ; diagnostic différentiel ; dystrophie musculaire ; dystrophie musculaire facio-scapulo-humérale ; épidémiologie ; étiologie ; histoire naturelle de la maladie ; maladie neuromusculaire ; prise en charge thérapeutique Résumé : Initial Posting: March 8, 1999; Last Update: February 6, 2020.
Facioscapulohumeral muscular dystrophy (FSHD) typically presents with weakness of the facial muscles, the stabilizers of the scapula, or the dorsiflexors of the foot. Severity is highly variable. Weakness is slowly progressive and approximately 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened.
The diagnosis of FSHD1 is established in a proband with characteristic clinical features by identification of a heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a chromosome 4 permissive haplotype. The diagnosis of FSHD2 is established in a proband by identification of hypomethylation of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a chromosome 4 permissive haplotype. Hypomethylation of the D4Z4 repeat array can be due to a heterozygous pathogenic variant in SMCHD1 or DNMT3B.
Treatment of manifestations: Consultation with a physical therapist to establish appropriate exercise regimen; ankle/foot orthoses to improve mobility and prevent falls; occupational and speech therapy in individuals with infantile onset; surgical fixation of the scapula to the chest wall may improve range of motion of the arms over the short term; management of chronic pain by physical therapy and medication; monitoring respiratory function; lubricants to prevent drying of the sclera or taping the eyes shut during sleep to treat exposure keratitis; treatment for retinal vasculopathy as per ophthalmologist; standard treatment of sensorineural hearing loss.
Surveillance: Annual physical therapy assessment; Pain should be assessed at regular visits to the primary care physician or physical therapist; screening for hypoventilation in individuals with abnormal PFTs, severe proximal weakness, kyphoscoliosis, wheelchair dependence, or comorbid disease affecting ventilation; pulmonary consultation for FVC
FSHD1 is inherited in an autosomal dominant manner. Approximately 70%-90% of individuals have inherited the disease-causing deletion from a parent, and approximately 10%-30% of affected individuals have FSHD as the result of a de novo deletion. Offspring of an affected individual have a 50% chance of inheriting the deletion. Prenatal testing for pregnancies at increased risk is possible if the D4Z4 pathogenic contraction has been identified in the family. FSHD2 is inherited in a digenic manner.
Lien associé : Texte complet disponible en accès libre sur Bookshelf GeneReviews® Pubmed / DOI : Pubmed : 20301616 N° Profil MNM : 2020021 En ligne : http://www.ncbi.nlm.nih.gov/pubmed/20301616Rosenberg H, Sambuughin N, Riazi S, et al.
GeneReviews® [Internet], 2020
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