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Pediatric Neurology Jul 2022Hereditary hyperekplexia (HPX) is a genetic neurodevelopmental disorder recently defined by the triad of (1) neonatal hypertonia, (2) excessive startle reflexes, and (3)... (Review)
Review
Hereditary hyperekplexia (HPX) is a genetic neurodevelopmental disorder recently defined by the triad of (1) neonatal hypertonia, (2) excessive startle reflexes, and (3) generalized stiffness following the startle. Defects in GLRA1 are the most common cause of HPX, inherited both in an autosomal dominant and autosomal recessive manner. GLRA1 mutations can also cause milder phenotypes in the startle syndromes spectrum, but the prevalence is uncertain and no clear genotype-phenotype correlation has emerged yet. Moreover, the prevalence of neurodevelopmental outcomes has not been clearly defined. Here we report a new family of patients with a typical HPX phenotype, linked to a novel GLRA1 mutation, inherited with a recessive pattern. We then perform a systematic review of the literature of GLRA1-related HPX, describing the main epidemiological features of 210 patients. We found that GLRA1-related phenotypes do not necessarily fulfill the current criteria for HPX, including also milder and later-onset phenotypes. Among clinical features of the disease, neurodevelopmental issues were reported in a third of the sample; interestingly, we found that these problems, particularly when severe, were more common in homozygous than in heterozygous patients. Additional clinical and preclinical studies are needed to define predictors of adverse neurodevelopmental outcomes and underlying mechanisms.
Topics: Humans; Muscle Rigidity; Phenotype; Receptors, Glycine; Reflex, Startle; Stiff-Person Syndrome
PubMed: 35636282
DOI: 10.1016/j.pediatrneurol.2022.05.002 -
Acta Neurologica Scandinavica Feb 2019Hereditary transthyretin(TTR)-related amyloidosis (ATTRm amyloidosis) is an endemic/non-endemic, autosomal-dominant, early- and late-onset, rare, progressive disorder,...
Hereditary transthyretin(TTR)-related amyloidosis (ATTRm amyloidosis) is an endemic/non-endemic, autosomal-dominant, early- and late-onset, rare, progressive disorder, predominantly manifesting as length-dependent, small fiber dominant, axonal polyneuropathy and frequently associated with cardiac disorders and other multisystem diseases. ATTRm amyloidosis is due to variants in the TTR gene, with the substitution Val30Met as the most frequent mutation. TTR mutations lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, and formation of amyloid fibrils, which are consecutively deposited extracellularly in various tissues, such as nerves, heart, brain, eyes, intestines, kidneys, or the skin. Neuropathy may not only include large nerve fibers but also small fibers, and not only sensory and motor fibers but also autonomic fibers. Types of TTR variants, age at onset, penetrance, and clinical presentation vary between geographical areas. Suggestive of a ATTRm amyloidosis are a sensorimotor polyneuropathy, positive family history, autonomic dysfunction, cardiomyopathy, carpal tunnel syndrome, unexplained weight loss, and resistance to immunotherapy. If only sensory A-delta or C fibers are affected, small fiber neuropathy ensues. Diagnostic tests for small fiber neuropathy include determination of intraepidermal nerve fiber density, laser-evoked potentials, heat- and cold-detection thresholds, and measurement of the electrochemical skin conductance. Therapy currently relies on liver transplantation and TTR-stabilizers (tafamidis, diflunisal).
Topics: Amyloid Neuropathies, Familial; Humans; Mutation; Prealbumin
PubMed: 30295933
DOI: 10.1111/ane.13035 -
Blood Coagulation & Fibrinolysis : An... Jul 2013May-Hegglin anomaly (MHA) is an autosomal dominant disorder, characterized by a variable degree of thrombocytopaenia, large platelets and inclusion bodies in white blood... (Review)
Review
May-Hegglin anomaly (MHA) is an autosomal dominant disorder, characterized by a variable degree of thrombocytopaenia, large platelets and inclusion bodies in white blood cells. Bleeding manifestations are generally mild, but severe bleeding episodes have been reported. This is a systematic review of literature for MHA during pregnancy. The review revealed 26 articles (25 case reports and one case series) including 75 pregnancies (five twin pregnancies) in 40 women. In 11 women, first presentation was incidental thrombocytopaenia during routine antenatal blood test. Of these, five women were misdiagnosed as idiopathic thrombocytopenic purpura (ITP), including three who underwent splenectomy for resistant ITP. Postpartum haemorrhage (PPH) and bleeding after miscarriage were presenting symptoms in two women. Antiplatelet antibody was found in three pregnancies. Only one of them required intervention with intravenous immunoglobulin (IVIG) to prevent neonatal alloimmune thrombocytopaenia. PPH was reported in four pregnancies; three were primary PPH, of which one had blood transfusion, one had platelet and cryoprecipitate transfusion and the third was managed conservatively. There was one secondary PPH that was treated conservatively. Neonatal outcome included 78 live neonates and two intrauterine fetal deaths. Thirty-four neonates had thrombocytopaenia and subsequently were diagnosed with MHA, three of them required platelet transfusion prophylactically as they developed very low platelet counts and one neonate with platelet count of 29 × 10 cells/l and received IVIG, as the mother had a positive antiplatelet antibody during pregnancy. No obvious bleeding complications were reported among the neonates. MHA can present challenges during pregnancy and be associated with adverse maternal and neonatal outcome because of bleeding complications. Joint management by obstetrician and haematologists is required to minimize these risks.
Topics: Abortion, Spontaneous; Antiplatyhelmintic Agents; Autoantibodies; Blood Platelets; Diagnosis, Differential; Female; Hearing Loss, Sensorineural; Humans; Infant, Newborn; Platelet Count; Platelet Transfusion; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Thrombocytopenia, Neonatal Alloimmune
PubMed: 23811802
DOI: 10.1097/MBC.0b013e32835fad03 -
Orphanet Journal of Rare Diseases Jun 2023CSF1R mutations cause autosomal-dominant CSF1R-related leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) and autosomal-recessive brain... (Review)
Review
CSF1R mutations cause autosomal-dominant CSF1R-related leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) and autosomal-recessive brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). The former is increasingly recognized, and disease-modifying therapy was introduced; however, literature is scarce on the latter. This review analyzes BANDDOS and discusses similarities and differences with CSF1R-ALSP.We systematically retrieved and analyzed the clinical, genetic, radiological, and pathological data on the previously reported and our cases with BANDDOS. We identified 19 patients with BANDDOS (literature search according to the PRISMA 2020 guidelines: n = 16, our material: n = 3). We found 11 CSF1R mutations, including splicing (n = 3), missense (n = 3), nonsense (n = 2), and intronic (n = 2) variants and one inframe deletion. All mutations disrupted the tyrosine kinase domain or resulted in nonsense-mediated mRNA decay. The material is heterogenous, and the presented information refers to the number of patients with sufficient data on specific symptoms, results, or performed procedures. The first symptoms occurred in the perinatal period (n = 5), infancy (n = 2), childhood (n = 5), and adulthood (n = 1). Dysmorphic features were present in 7/17 cases. Neurological symptoms included speech disturbances (n = 13/15), cognitive decline (n = 12/14), spasticity/rigidity (n = 12/15), hyperactive tendon reflex (n = 11/14), pathological reflexes (n = 8/11), seizures (n = 9/16), dysphagia (n = 9/12), developmental delay (n = 7/14), infantile hypotonia (n = 3/11), and optic nerve atrophy (n = 2/7). Skeletal deformities were observed in 13/17 cases and fell within the dysosteosclerosis - Pyle disease spectrum. Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10). Three patients died in infancy, two in childhood, and one case at unspecified age. A single brain autopsy evidenced multiple brain anomalies, absence of corpus callosum, absence of microglia, severe white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications.In conclusion, BANDDOS presents in the perinatal period or infancy and has a devastating course with congenital brain abnormalities, developmental delay, neurological deficits, osteopetrosis, and dysmorphic features. There is a significant overlap in the clinical, radiological, and neuropathological aspects between BANDDOS and CSF1R-ALSP. As both disorders are on the same continuum, there is a window of opportunity to apply available therapy in CSF1R-ALSP to BANDDOS.
Topics: Humans; Neuroglia; Leukoencephalopathies; Brain; Mutation; Nervous System Malformations; Atrophy
PubMed: 37349768
DOI: 10.1186/s13023-023-02772-9 -
Current Pediatric Reviews 2023Silver-Russell syndrome (SRS) is a developmental disorder involving extreme growth failure, characteristic facial features and underlying genetic heterogeneity. As the...
BACKGROUND
Silver-Russell syndrome (SRS) is a developmental disorder involving extreme growth failure, characteristic facial features and underlying genetic heterogeneity. As the clinical heterogeneity of SRS makes diagnosis a challenging task, the worldwide incidence of SRS could vary from 1:30,000 to 1:100,000. Although various chromosomal, genetic, and epigenetic mutations have been linked with SRS, the cause had only been identified in half of the cases.
MATERIAL AND METHODS
To have a better understanding of the SRS clinical presentation and mutation/ epimutation responsible for SRS, a systematic review of the literature was carried out using appropriate keywords in various scientific databases (PROSPERO protocol registration CRD42021273211). Clinical features of SRS have been compiled and presented corresponding to the specific genetic subtype. An attempt has been made to understand the recurrence risk and the role of model organisms in understanding the molecular mechanisms of SRS pathology, treatment, and management strategies of the affected patients through the analysis of selected literature.
RESULTS
156 articles were selected to understand the clinical and molecular heterogeneity of SRS. Information about detailed clinical features was available for 228 patients only, and it was observed that body asymmetry and relative macrocephaly were most prevalent in cases with methylation defects of the 11p15 region. In about 38% of cases, methylation defects in ICRs or genomic mutations at the 11p15 region have been implicated. Maternal uniparental disomy of chromosome 7 (mUPD7) accounts for about 7% of SRS cases, and rarely, uniparental disomy of other autosomes (11, 14, 16, and 20 chromosomes) has been documented. Mutation in half of the cases is yet to be identified. Studies involving mice as experimental animals have been helpful in understanding the underlying molecular mechanism. As the clinical presentation of the syndrome varies a lot, treatment needs to be individualized with multidisciplinary effort.
CONCLUSION
SRS is a clinically and genetically heterogeneous disorder, with most of the cases being implicated with a mutation in the 11p15 region and maternal disomy of chromosome 7. Recurrence risk varies according to the molecular subtype. Studies with mice as a model organism have been useful in understanding the underlying molecular mechanism leading to the characteristic clinical presentation of the syndrome. Management strategies often need to be individualized due to varied clinical presentations.
Topics: Humans; Animals; Mice; Mice, Inbred ICR; Silver-Russell Syndrome; Uniparental Disomy; Genomic Imprinting
PubMed: 35293298
DOI: 10.2174/1573396318666220315142542 -
The British Journal of Dermatology Apr 2016Buschke-Ollendorff syndrome (BOS) is a rare, often benign, autosomal skin disorder. BOS commonly presents with nontender connective tissue naevi and sclerotic bony... (Review)
Review
Buschke-Ollendorff syndrome (BOS) is a rare, often benign, autosomal skin disorder. BOS commonly presents with nontender connective tissue naevi and sclerotic bony lesions (osteopoikilosis [OPK]). Herein, we summarize the presenting features of BOS and potential associations by conducting a systematic review of the literature and summarizing a cohort seen at the Hospital for Sick Children (HSC), Toronto, Canada. PubMed was searched using the following terms: 'BOS'; 'dermatofibrosis lenticularis'; 'OPK'; 'LEMD3'; 'elastoma'; 'collagenoma'. Only case reports were included, without date or language restrictions. Cases were further narrowed to those where patients or their families had a combination of skin and bony lesions, or a positive genetic test. Data were summarized using frequencies. In total, 594 reports were discovered, of which 546 (92%) were excluded. The remaining 48 accounted for 164 cases. Skin lesions were noted in 24% of cases and bony lesions in 20%, while 54% of patients had both. In 1% of cases the diagnosis was made on genetic testing alone. A family history was noted in 92% of cases. All patients with spinal stenosis (2%) or shortened status (7%) had OPK. Six per cent of patients had neurological problems. However, 50% of the cohort from HSC had cognitive delays, and only cases from 2007 onwards reported cognitive delays (the prevalence was 17% among those cases). This review confirms the classical diagnostic features of BOS. In addition, it highlights a previously unreported association between a shortened stature and OPK, as well as a possible association with cognitive delays.
Topics: Adolescent; Adult; Age Distribution; Age of Onset; Aged; Child; Female; Humans; Male; Middle Aged; Osteopoikilosis; Skin Diseases, Genetic; Young Adult
PubMed: 26708699
DOI: 10.1111/bjd.14366 -
Neurology. Clinical Practice Dec 2020Migraine is a common and often refractory feature for individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy... (Review)
Review
BACKGROUND
Migraine is a common and often refractory feature for individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) without consensus guidelines for treatment. Migraine treatment poses a theoretical risk within this unique population with precarious cerebrovascular autoregulation, given the vasomodulatory influence of many antimigraine medications. In this systematic review and meta-analysis, we evaluate the frequency and efficacy of treatments for migraine in individuals with CADASIL.
METHODS
A search protocol was designed to include all available publications reporting antimigraine therapies for CADASIL. Individual responses to medications were categorized as unfavorable, neutral, or favorable. Responses across medication classes were compared using the Mann-Whitney test.
RESULTS
Thirteen studies were included, yielding a cohort of 123 individuals with a median age of 53 years (range: 23-83 years), with 61% (75/123) being women. No controlled trials were identified. Simple analgesics (35.8%, 44/123) and beta-blockers (22.0%, 27/123) were the most common abortive and prophylactic strategies, respectively. Over half (54.4%) of all patients had used more than 1 medication sequentially or concomitantly. Beta-blockers were significantly associated with a neutral or unfavorable response (13.5%, 22/163, = 0.004). We found no significant associations among other medication categories.
CONCLUSIONS
Migraine in CADASIL remains a formidable therapeutic challenge, with patients often tried on several medications. Antimigraine prophylaxis with beta-blockers may be contraindicated relative to other common therapies in CADASIL. Controlled studies are needed to rigorously evaluate the safety and efficacy of antimigraine therapies in this population.
PubMed: 33520412
DOI: 10.1212/CPJ.0000000000000769 -
Haemophilia : the Official Journal of... Sep 2011Glanzmann Thrombasthenia (GT) is a rare autosomal recessive disorder which usually manifests as severe mucocutaneous bleeding and is caused by deficiency of the platelet... (Review)
Review
Glanzmann Thrombasthenia (GT) is a rare autosomal recessive disorder which usually manifests as severe mucocutaneous bleeding and is caused by deficiency of the platelet glycoprotein IIb-IIIa. Pregnancy in women with GT presents particular challenges as there is increased risk of both maternal and foetal bleeding. To improve understanding and clarify the optimum management of pregnancy in this disorder, we performed a systematic review of the world literature of pregnancy and GT. This identified three single-centre case series of patients with GT that included brief descriptions of women in pregnancy and 31 detailed case reports of 40 pregnancies in 35 women that resulted in 38 live births. Among the detailed case reports, ante-natal bleeding was described in 50% of pregnancies but was usually mild and occurred at mucocutaneous sites. Primary postpartum haemorrhage (PPH) was reported in 34% of pregnancies and secondary PPH in 24%. PPH was frequently severe and occurred up to 20 days after delivery. There was a wide variation in approach to prevention and treatment of PPH but most women received platelet transfusion, sometimes with additional recombinant FVIIa and anti-fibrinolytics. Maternal alloimmunization against platelet antigens was reported in 73% of pregnancies and was associated with four neonatal deaths. These data emphasize the need for multidisciplinary management of pregnancy in women with GT. Delivery plans should recognize the need for prevention and aggressive treatment of PPH and should minimize foetal bleeding risk in pregnancies complicated by alloimmunization.
Topics: Antifibrinolytic Agents; Disease Management; Factor VIIa; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Obstetric Labor Complications; Platelet Transfusion; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Recombinant Proteins; Thrombasthenia
PubMed: 21457404
DOI: 10.1111/j.1365-2516.2011.02516.x -
Cerebellum (London, England) Jun 2024Spinocerebellar ataxias (SCAs) are a heterogenous group of rare neurodegenerative conditions sharing an autosomal dominant pattern of inheritance. More than 40 SCAs have... (Review)
Review
Spinocerebellar ataxias (SCAs) are a heterogenous group of rare neurodegenerative conditions sharing an autosomal dominant pattern of inheritance. More than 40 SCAs have been genetically determined. However, a systematic review of SCA epidemiology in Europe is still missing. Here we performed a narrative review of the literature on the epidemiology of the most common SCAs in Europe. PubMed, Embase, and MEDLINE were searched from inception until 1 April 2023. All English peer-reviewed articles published were considered and then filtered by abstract examination and subsequently by full text reading. A total of 917 original articles were retrieved. According to the inclusion criteria and after reviewing references for useful papers, a total of 35 articles were included in the review. Overall, SCA3 is the most frequent spinocerebellar ataxia in Europe. Its frequency is strikingly higher in Portugal, followed by Germany, France, and Netherlands. None or few cases were described in Italy, Russia, Poland, Serbia, Finland, and Norway. SCA1 and SCA2 globally displayed similar frequencies, and are more prevalent in Italy, United Kingdom, Poland, Serbia, and France.
Topics: Humans; Spinocerebellar Ataxias; Europe; Prevalence
PubMed: 37698771
DOI: 10.1007/s12311-023-01600-x -
Pediatric Research Jul 2021Congenital chloride diarrhea (CLD) is a rare autosomal recessive disorder characterized by watery diarrhea with a high level of fecal Cl, metabolic alkalosis, and...
INTRODUCTION
Congenital chloride diarrhea (CLD) is a rare autosomal recessive disorder characterized by watery diarrhea with a high level of fecal Cl, metabolic alkalosis, and electrolyte alterations. Several intestinal and extraintestinal complications and even death can occur. An optimal knowledge of the clinical features and best therapeutic strategies is mandatory for an effective management.
METHODS
Articles published between 1 January 1965 and 31 December 2019, reported in PUBMED and EMBASE, were evaluated for a systematic review analyzing four categories: anamnestic features, clinical features, management, and follow-up strategies.
RESULTS
Fifty-seven papers reporting information on 193 CLD patients were included. The most common anamnestic features were positive family anamnesis for chronic diarrhea (44.4%), consanguinity (75%), polyhydramnios (98.3%), preterm delivery (78.6%), and failure to pass meconium (60.7%). Mean age at diarrhea onset was 6.63 days. Median diagnostic delay was 60 days. Prenatal diagnosis, based on molecular analysis, was described in 40/172 (23.3%). All patients received NaCl/KCl-substitutive therapy. An improvement of diarrhea during adulthood was reported in 91.3% of cases. Failure to thrive (21.6%) and chronic kidney disease (17.7%) were the most common complications.
CONCLUSIONS
This analysis of a large population suggests the necessity of better strategies for the management of CLD. A close follow-up and a multidisciplinary approach is mandatory to manage this condition characterized by heterogeneous and multisystemic complications.
IMPACT
In this systematic review, we describe data regarding anamnestic features, clinical features, management, and follow-up of CLD patients obtained from the largest population of patients ever described to date. The results of our investigation could provide useful insights for the diagnostic approach and the management of this condition.
Topics: Diarrhea; Feces; Humans; Infant, Newborn; Meconium; Metabolism, Inborn Errors; Mutation, Missense
PubMed: 33173177
DOI: 10.1038/s41390-020-01251-2