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We report a patient with a de novo interstitial deletion of the long arm of chromosome 2 involving bands 2q24.3-q31.1. The patient shows postnatal growth retardation, microcephaly, ptosis, down-slanting palpebral fissures, long eyelashes and micrognathia. Halluces are long, broad and medially deviated, while the other toes are laterally deviated and remarkably short with hypoplastic phalanges. She also showed developmental delay, seizures, lack of eye contact, stereotypic and repetitive hand movements and sleep disturbances with breath holding. Prenatal and three independent postnatal karyotypes were normal. Array-CGH analysis allowed us to identify and characterize a "de novo" 2q interstitial deletion of about 10.4Mb, involving segment between cytogenetic bands 2q24.3 and 2q31.1. The deletion was confirmed by quantitative PCR. About 30 children with 2q interstitial deletion have been reported. The deletion described here is overlapping with 15 of these cases. We have attempted to compare the clinical features of our patient with 15 overlapping cases. The emerging phenotypes include low birth weight, postnatal growth retardation, mental retardation and developmental delay, microcephaly, and peculiar facial dysmorphisms. Peculiar long and broad halluces with an increased distance between the first and the second toe are ("sandal gap" sign) present in most of the described patients. The gene content analysis of the deleted region revealed the presence of some genes that may be indicated as good candidates in generating both neurological and dysmorphic phenotype in the patient. In particular, a cluster of SCNA genes is located within the deleted region and it is known that loss of function mutations in SCNA1 gene cause a severe form of epilepsy.
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PMID:2q24-q31 deletion: report of a case and review of the literature. 1708 12

Patients harboring A467T and W748S POLG1 mutations present with a broad variety of neurological phenotypes, including cerebellar ataxia, progressive external ophthalmoplegia (PEO), myoclonus, epilepsy, and peripheral neuropathy. With exception of ataxia and myoclonus, movement disorders are not typical features of POLG1 associated disorders. We report on two affected siblings compound heterozygous for A467T and W748S mutations, one suffering from choreoathetosis and apraxia of lid opening due to focal eyelid dystonia that mimicked progression of ptosis, resulting in functional blindness. So far, focal dystonia has not been reported in POLG1 mutation carriers, and should be considered when investigating patients with PEO and ptosis. Further studies on POLG1 mutations in focal dystonia are warranted.
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PMID:Apraxia of lid opening mimicking ptosis in compound heterozygosity for A467T and W748S POLG1 mutations. 1854 43

An 11-year-old girl manifested with photophobia, ptosis, external ophthalmoplegia, hypotonia, weakness of proximal limb muscles, hyporeflexia, and generalized seizures (six months). Her elder sister had had uncontrolled seizures and photophobia and died at seven years of age. In the patient, serum lactate was high (55 mg/dl). Muscle biopsy revealed characteristic ragged red and ragged blue fibers, diagnostic of mitochondrial cytopathy. Sequencing of the complete mitochondrial genome of the DNA obtained from the muscle biopsy of the patient did not show any characteristic mutation. Four months later, the girl was admitted with a one-week history of epilepsia partialis continua (EPC). EEG revealed Periodic Lateralized Epileptiform Discharges (PLEDs), once in 2-4 seconds, over the right temporo-occipital leads. MRI revealed signal change of right motor cortex, which had restricted diffusion. MR spectroscopy (MRS) from this region revealed lactate peak. EPC remained refractory to multiple anti-epileptic drugs, immuno-modulators, coenzyme-Q, and carnitine. This thought provoking report expands the spectrum of mitochondrial cytopathies.
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PMID:Epilepsia partialis continua in mitochondrial dysfunction: Interesting phenotypic and MRI observations. 1989 69

Toxoplasmosis is a rare opportunistic protozoal infection, which may occur in patients after hematopoietic stem cell transplantation. This disease originates almost exclusively from reactivation of latent infection in seropositive recipients. We present a case report of one patient with diagnosis of acute myeloid leukemia undergoing two allogeneic stem cell transplantations at two years interval. The second transplantation was complicated by the development of the toxoplasmic encephalitis in early posttransplant course. The initial neurological symptoms included diplopia caused by the paresis of right side motor branches of the 3rd and 6th cranial nerves due to a compressive lesion in basal ganglia. Patient suddenly deteriorated after an epileptic seizure followed by a loss of consciousness, bilateral ptosis and right side mydriasis. Prolonged sopor and bilateral mydriasis appeared because of the further lesion progression in basal ganglia and compression of the 3rd cranial nerve. After targeted therapy of Toxoplasma gondii the patient's clinical status improved and she regained consciousness. Unfortunately, examination of bone marrow later revealed the relapse of leukemia. We compared risk factors of the latent reactivation of infection in immunocompromised patients with published data. It is of interest that the toxoplasmosis of the brain developed in this patient after the second transplantation.
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PMID:[Toxoplasmosis of the central nervous systems after allogeneic stem cell transplantation]. 2051 52

An 11-year-old girl and a 25-year-old woman were both initially referred to a neurologist with 'common' neurological problems: The girl suffered from tics, and later epilepsy, and her serum lactate concentration was elevated. She had unilateral hyperintensity of the left cerebral cortex and later developed diabetes mellitus. The woman had muscle weakness, diabetes mellitus and ptosis. In both patients, the problems turned out to be an expression of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). The first patient died at 18 years of age during an epileptic seizure with severe metabolic disturbances. The second patient developed bilateral perceptive hearing loss, epilepsy and cardiomyopathy and she was repeatedly admitted to hospital with stroke-like episodes. She died at 46 years of age. Both patients had the MELAS A3243G point mutation. MELAS is a maternally inherited mitochondrial disorder. The age of onset and symptoms are highly variable, even within one family. To date there are no curative treatment options for the disease. Diagnosing MELAS is important though, for optimising the treatment of the individual symptoms and genetic counselling.
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PMID:[Unexceptional symptoms as expression of MELAS]. 2108 56

In about 30% of the patients with syndromal craniosynostosis, a genetic mutation can be traced. For the purpose of adequate genetic counseling and treatment of these patients, the full spectrum of clinical findings for each specific mutation needs to be appreciated. The Pro250Arg mutation in the FGFR3 gene is found in patients with Muenke syndrome and is one of the most frequently encountered mutations in craniosynostosis syndromes. A number of studies on the relationship between genotype and phenotype concerning this specific mutation have been published. Two Dutch families with Muenke syndrome were screened for the reported characteristics of this syndrome and for additional features. New phenotypical findings were hypoplasia of the frontal sinus, ptosis of the upper eyelids, dysplastic elbow joints with restricted elbow motion, and mild cutaneous syndactyly. Incidentally, polydactyly, severe ankylosis of the elbow, fusion of cervical vertebrae, and epilepsy were found. Upper eyelid ptosis is thought to be pathognomonic for Saethre-Chotzen syndrome but was also observed in our series of patients with Muenke syndrome. Because Muenke and Saethre-Chotzen syndrome can have similar phenotypes, DNA analysis is needed to distinguish between these syndromes, even when a syndrome diagnosis is already made in a family member.
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PMID:Additional phenotypic features of Muenke syndrome in 2 Dutch families. 2140 57

We report the case of a 5-year-old boy with multiple congenital anomalies, including ptosis, polydactyly, ventricular septal defect, epilepsy, and intellectual deficits. The patient presented with synkinetic eyelid movements accompanying jaw and ocular movements, including Marcus-Gunn phenomenon (eyelid elevation at mouth opening) in the right eye, inverse Marcus-Gunn phenomenon (aggravation of ptosis at mouth opening) in the left eye, and unilateral eyelid elevation on each side during ipsilateral abduction. This suggests that the different types of synkinesia may represent a common etiology of aberrant innervations and/or reflex phenomena of the cranial nerves caused by a specific genetic defect.
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PMID:Concurrence of multiple types of eyelid synkinesia in a patient with congenital anomalies. 2143 6

Aicardi syndrome is a rare neurodevelopmental disorder characterized by corpus callosum agenesis, chorioretinal lacunae and early-onset infantile spasms. We report a particular case of Aicardi syndrome characterized by the association of the classical triad of severe bilateral ptosis, pontocerebellar hypoplasia, and perisylvian polymicrogyria in a girl born to non-consanguineous parents, but whose mother suffered from idiopathic generalized epilepsy.
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PMID:[Aicardi syndrome associated with severe congenital ptosis]. 2182 Feb 92

We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.
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PMID:Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats. 2194 86

We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C) in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7). Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28), a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2(Y616C) gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2(Y616C) complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other "mitochondrial" features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias.
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PMID:Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. 2202 84


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