158 research outputs found
Laser interstitial thermal therapy in pediatric cerebellar epilepsy
Cerebellar lesional epilepsy is rare, commonly manifesting in early life and posing diagnostic and treatment challenges. Seizure semiology may be subtle, with repetitive eye blinking, face twitching, and irregular breathing, while EEG commonly remains unremarkable. Pharmacoresistance is the rule, and surgical intervention is the only treatment with the potential for cure. Novel minimally invasive techniques, such as laser interstitial thermal therapy (LITT), are emerging for surgically less accessible, deep-seated epileptogenic lesions. We report the case of a patient who presented with peculiar eye and face movements occurring episodically and stereotypically since the first weeks of life and was later diagnosed with cerebellar epilepsy related to a hamartoma. Refractory daily seizures, unresponsive to antiseizure medication, were followed by increasingly prominent gait ataxia and delayed speech development. Staged LITT was performed in two consecutive sessions at 3 and 4 years, leading to seizure cessation, neurological improvement, and developmental gains over a postsurgical follow-up period of 8 months. Our case highlights cerebellar lesional epilepsy as a rare but important differential diagnosis in children with paroxysmal disorders predominantly involving the face. Furthermore, we illustrate the radiological correlates of neurocognitive deficit related to the cerebellar lesion, manifesting as cerebello-cerebral diaschisis. Most importantly, our observations showcase LITT as a safe and effective therapeutic approach in cerebellar lesional epilepsy and an attractive alternative to open brain surgery, especially for deep-seated lesions in the pediatric population
Am J Hum Genet
Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the γ-subunit gene (CHRNG) of the AChR. Our functional studies show that γ-subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney–cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two α, one β, and one δ subunit are always present. By switching γ to ϵ subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the γ subunit were thought to be lethal, as they are in γ-knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because γ expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway
Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome
Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome wide siRNA screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies
MKS3/TMEM67 mutations are a major cause of COACH syndrome, a joubert syndrome related disorder with liver involvement
The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/
aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the
“molar tooth sign”, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs
Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.
CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder
Boldness and predator deterrence: a critique of Godin & Davis
Godin & Davis (1995) claimed to have provided experimental evidence for a predator pursuit deterrence function of predator inspection in the guppy. We doubt that they have shown that inspection behaviour per se deters attack because their evidence is actually correlational and thus inherently ambiguous; furthermore we think their methods are flawed
Severe neurological impairment in hereditary methaemoglobinaemia type 2
Recessive congenital methaemoglobinaemia (RCM) due to NADH-cytochrome b5 reductase (cytb5r) deficiency is a very rare disorder. We report on two unrelated patients (4 and 2.5 years old) with RCM type 2. Developmental delay was obvious at the age of 4 months. On follow-up, both children showed severe tetraspastic cerebral palsy, profound cognitive impairment, strabismus, impressive secondary microcephaly and failure to thrive. One novel mutation in the DIA1gene was identified. Prenatal diagnosis was successfully done in both families by mutation analysis in chorionic villi or measurement of cytb5r in fetal amniotic cells. Conclusion:due to the severity of this disease and its 25% recurrence risk, prenatal diagnosis should be made available to all affected familie
Ophthalmologic findings and long-term course in patients with neurofibromatosis type 2
PURPOSE: To evaluate ophthalmologic findings and long-term course in patients with neurofibromatosis type 2 (NF2). DESIGN: Retrospective observational case series. METHODS: SETTING: Single-center institutional practice. STUDY POPULATION: Thirty referred patients with NF2 were enrolled from 1991 to 2003 and underwent at least one thorough neuroophthalmologic examination. Follow-up of 23 patients ranged from 4.3 to 12.5 years. MAIN OUTCOME MEASURES: Visual function, structural ocular abnormalities, onset and type of presenting NF2-related symptoms, and number of central nervous system tumors. RESULTS: Initial symptoms for patients with early-onset NF2 mostly comprised ophthalmologic symptoms (n = 7) and lower motor neuron extremity weakness (n = 6), as opposed to eighth nerve impairment (n = 11) in late disease onset. NF2-specific ocular findings were noted in 83% of all patients (94% childhood onset; 67% adult onset): 67% had cataracts, 40% epiretinal membranes, 3% hamartoma, 13% disk gliomas, and 27% optic nerve sheath meningiomas. Only 14% in the childhood-onset group-as opposed to 78% in the adult-onset group-sustained visual acuity of 1.0 in both eyes at final examination. Significantly more patients with early onset of symptoms developed multiple central nervous system tumors (P = .004) and showed a higher amount of NF2-specific findings (P = .015). CONCLUSIONS: Initial manifestations of NF2 differ between children and adults. NF2-specific ophthalmologic findings can help establish the diagnosis. Symptom onset at a young age is clearly a risk factor for marked disease progression. These patients should be carefully followed because survival rates have increased, and vision becomes increasingly important as the disease progresses
Prediction of the clinical outcome of cavernous sinus lesions in children
To identify predictive findings in children with nontraumatic acquired cavernous sinus lesions, a retrospective study of the clinical course of 4 of our own patients and 17 more children found in an extensive literature search was performed. Mean age was 8.7 years. Malignancy was found in 11 of 21 children (6 female, 15 male). Of these 21 children, 9 were cured, 8 are either in remission or their course is unknown, and 4 died. Eight of the nine cured patients were diagnosed as having had Tolosa-Hunt syndrome. Of the four deceased children, three had a very short course (1 to 4 months) and were diagnosed with malignant lymphoma (n = 2) and rhabdomyosarcoma (n = 1). One patient died from a brain tumor other than the initially diagnosed T-cell lymphoma in the cavernous sinus after a follow-up of 8 years. MRI should be the preferred imaging technique—even if it is not conclusive in many cases—and every possible diagnostic effort should be made before using corticosteroids. No clinical or radiological signs other than rapid deterioration seem to be predictable of a malignant cavernous sinus lesion with poor outcome. Thus, close follow-up is recommended in children with signs and symptoms indicative of an acquired lesion in the cavernous sinus
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