Habitual seizures started at 10 years. Seizures were never controlled despite several antiepileptic drug regimes. On EEG-videotelemetry, four habitual partial seizures were recorded; lateralising semiological signs included nose rubbing with his right hand and post-ictal urinary urge; ictal EEG showed bitemporal rhythmic theta discharge, more prominent and sustained on the right, with right temporal interictal epileptiform discharges.
Neuropsychometry showed mild learning disability, globally weak memory, but low risk of global amnesia in the context of left temporal structural normality. At 28, he had a right anterior temporal lobectomy. He has been free of seizures to the more recent follow-up at 36 months, with tapering of antiepileptic drugs. Repeat neuropsychometric assessment showed improvement of attention span, verbal memory and spatial reasoning skills; his visual memory and higher-level visual processing skills had slightly declined.
Histopathology of the lobectomy specimen confirmed hippocampal sclerosis, without mossy fibre sprouting Figure S2. He was considered to have surgically-remediable, typical sporadic mesial temporal lobe epilepsy due to hippocampal sclerosis. The medical history was otherwise unremarkable. PROS1 mutations and deletions cause autosomal dominant hereditary thrombophilia .
Given the unexplained early cerebral infarction, we suspected protein S functional deficiency, since thrombophilia is a stroke risk factor in neonates and children . Case 1 had free and functional protein S deficiency respectively 0. The remainder of the thrombophilia screen, including antiphospholipid antibodies, which may induce acquired protein S deficiency, yielded normal results.
Management consequences resulting from these findings comprised advice on risk reduction measures against thrombosis, including maintenance of hydration, avoidance of oestrogen-containing hormonal contraception, and low molecular-weight heparin thromboprophylaxis in situations with increased thrombotic risk. Long-term prophylactic anticoagulation was not indicated. On directed questioning after these findings, a family history of thrombophilia emerged.
Her maternal grandfather had had three known pulmonary emboli, from the age of 30 years, and had been anticoagulated until death at She has low free protein S 0. Such variable expressivity of PROS1 deletions is well known . Dense surface modelling analysis of the patient's face did not uncover facial dysmorphism Figure S4 , Video S1. KCNA1 encodes a voltage-gated delayed potassium channel K v 1. Nerve excitability testing in the patient showed several abnormalities Figure 1 which are also observed in patients with EA1 . However, the patient was on carbamazepine at the time of testing and therefore blockade of voltage-gated sodium channels may have contributed to some of the observed changes, which may not be solely due to reduced K v 1.
During needle electromyography the patient did not have fine involuntary finger movements and testing showed normal motor unit discharges despite obvious myokymia during other observations. In the nerve excitability profile, there was an abnormally enhanced late subexcitability of the recovery cycle A and a pronounced S2 accommodation and reduced TEd 90— ms value at the end of the depolarising threshold electrotonus upper trace in B. C,D : scatter plots of these nerve excitability parameters in the patient filled circle and 16 normal controls open symbols.
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See Text S1 for detailed description of methods. KCNA5 encodes a voltage-gated potassium channel K v 1. KCNA5 loss-of-function mutations cause atrial fibrillation . Case 2 had had unprovoked, brief, paroxysmal episodes of fast palpitations, without other symptoms. On directed questioning, it emerged that her father deceased had had paroxysmal atrial fibrillation from his forties, and had been on treatment.
The patient's resting electrocardiogram and hour ambulatory electrocardiogram, both performed when she was asymptomatic, were normal. Further ECG monitoring is planned. VWF mutations cause von Willebrand disease, but incomplete penetrance is known . Factor VIII 1. Dense surface modelling analysis of the patient's face did not uncover facial dysmorphism Figure S4 , Video S2. HNF1B mutations and deletions cause renal cyst and diabetes syndrome  and hypomagnesemia .
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His HbA1c level, representing an integrated measure of glycemic control over the preceding days, was 5. Serum magnesium was low 0. Renal ultrasound showed bilateral cysts not shown. These findings fit with the known consequences of HNF1B deletion, but none were suspected or detected before discovery of the microdeletion. The metabolic profile for this patient is complex. Fasting total triglyceride levels were low 0. Acetyl-CoA carboxylation to malonyl-CoA cannot directly be measured in blood. However, its impairment could elevate citrate levels.
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Citrate is normally undetectable in urine. His fasting urine had no detectable citrate, but a sample after OGTT showed citraturia, compatible with hypercitratemia not measured. This suggests impaired citrate breakdown by ATP-citrate lyase, the enzyme responsible for this conversion, which may be overwhelmed by mass action from excess citrate production, as well as being impaired by a lack of insulin activation.
The alternative interpretation of an increased flux through the citrate synthetic tricarboxylic acid cycle pathway is unlikely, because his mitochondrial beta-oxidation is normal at rest and normally-suppressed through the OGTT as reflected by dynamic total and fractional acyl-carnitine levels, Figure S3. These observations are consistent with deficient ACC1 activity and with lack of dynamic activation of ACC1 in the context of an impaired insulin response. The absence of crotonyl derivatives on gas chromatography mass spectroscopy data not shown excludes a generalised functional biotin co-enzyme deficiency, which might have been an alternative explanation.
Consistent with disordered fat metabolism, his body build was lean body mass index BMI Re-inspection of his cranial MRI showed attenuation of subcutaneous fat deposits Figure 2. ACACA and ACLY the gene encoding ATP-citrate lyase are both known to be involved in lipogenesis in human adipose tissue and are regulated in a complex fashion by body energetics  , though we have not uncovered the precise mechanism in our patient. We note also that in a paediatric cohort of 11 patients with renal cysts sharing the same deletion  , wide variation of BMI was observed 2nd—th centile, median 67th centile , suggesting overall that variable expressivity and other factors contribute to BMI, which is a blunt phenotype.
His serum levels of fat-soluble vitamins A and E were normal. His low serum vitamin D level is difficult to interpret, possibly attributable to chronic therapy with enzyme-inducing antiepileptic drugs. A Coronal T2-weighted image showing the patient has attenuation of scalp subcutaneous fat arrows.
B Normal appearance in a patient with epilepsy without 17q12 deletion arrows.
Professor of Neurology at the Stanford University Medical Center
Subcutaneous scalp fat was present on cranial MRI in patients with temporal lobe epilepsy who did not carry this deletion. Ubiquinone deficiency is a cause of cerebellar ataxia, cerebellar atrophy or hypoplasia . The patient's father noted that the patient had always lacked dexterity and agility, being able as a child, for example, to run a sprint but not hurdles. His cranial MRI aged 28 showed mild cerebellar atrophy Figure 3. These findings are all in keeping with functional deficiency in ACC1, although an additional contribution from LHX1 deficiency cannot be excluded for the cerebellar phenotype .
Deficits in coordination and motor skills in patients with chromosome 17q12 deletion have been reported recently . T1-weighted MRI reveals cerebellar atrophy. Note this is a T1-weighted image not a T2-weighted image as in Figure 2A ; the bright layer in the scalp is diploe, not subcutaneous fat. The LHX1 gene, also residing in the deleted region, is a homeobox gene expressed in the developing brain and involved in neuronal differentiation  and cortical lamination . In mouse models, the Lhx1 gene is required for regulating the vertebrate head organizer .
Therefore, LHX1 emerges as a plausible candidate responsible for the neurological phenotypes in patients with chromosome 17q12 deletion  , possibly affecting brain development. Review of the tissue resected at temporal lobectomy of Case 3 showed a few cells deep in the temporal lobe white matter that contained abnormal storage material, that was PAS-positive, suggestive of excessive glycosylation Figure 4. The nature of the material could not be further clarified. No such changes have been noted in over other temporal lobectomy specimens resected from patients with drug-resistant mesial temporal lobe epilepsy .
However, cortical lamination, which we considered might have been affected by LHX1 deficiency, was normal when examined with several cortical layer markers Figure 5.
Neither have we detected any retinal abnormalities Text S1. In the deep white periventricular region of the temporal lobectomy specimen of Case 3, a single cluster of globoid cells with granular cytoplasm was present. The cells showed PAS positivity, which could indicate glycogen storage, but the cells did not contain myelin debris and there was no evidence of demyelination. The cells were only present focally. Further investigation regarding histogenesis of these cells and characterization of cytoplasmic contents was not possible.
Similar cell types were not noted in the hippocampus. Examination with several cortical layer markers antibodies against proteins denoted in each panel revealed normal cortical lamination in Case 3. Clinical genetic examination after discovery of the microdeletion showed subtle evidence of dysmorphism, not articulated by several neurologists during pre-surgical evaluation: he had a narrow face, mildly receding forehead, little facial subcutaneous fat, prominent nasal bridge, broad nasal base, long and wide philtrum and large mouth.
His shoulders were narrow, and he had pectus excavatum, limited elbow extension, flat hands, prominent finger joints, mild cutaneous 2—3 finger syndactyly, clinodactyly of the 5th fingers, under-developed hypothenar regions and narrow feet. Facial dysmorphism was confirmed by quantitative analysis in comparison with age-, sex- and ethnicity-matched controls Figure 6 , Video S3.
It should be emphasised that on first examination at our centre, facial abnormalities were not identified, and these were only documented by formal clinical genetics review and confirmed by quantitative analysis after discovery of the microdeletion. The scatter plot shows age horizontally against DSM distance vertically between the matched mean face and the patient and control faces. Distance from the patient-matched mean face was linearly regressed against age for all controls.
B Heat maps using a red—green-blue spectrum to depict inward—null-outward displacement along the surface normal for the patient face relative to its matched mean face using 50 control subjects.
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