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العنوان
Clinical, Biochemical and Molecular characterization among Egyptian Children with Methylmalonic acidemia /
المؤلف
Abdelgawad, Mohammad Emam Mohammad.
هيئة الاعداد
باحث / Mohammad Emam Mohammad Abdelgawad
مشرف / Alyaa Amal Kotby
مشرف / Ola Ali Khalifa
مناقش / Osama Kamal Zaki
تاريخ النشر
2019.
عدد الصفحات
106 P. :
اللغة
الإنجليزية
الدرجة
ماجستير
التخصص
علم الوراثة (السريرية)
تاريخ الإجازة
1/1/2019
مكان الإجازة
جامعة عين شمس - كلية الطب - قسم علم الوراثة
الفهرس
Only 14 pages are availabe for public view

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Abstract

Methylmalonic acidemia is an autosomal recessive disorder in which the body is unable to process certain proteins and fats properly. Signs and symptoms usually appear in early infancy and vary from mild to life-threatening. Affected infants can experience vomiting, hypotonia, developmental delay, lethargy, hepatomegaly, and failure to thrive. Long-term complications can include feeding problems, chronic kidney disease, optic atrophy, intellectual disability and pancreatitis. Without treatment, this condition can lead to coma and death in some cases.
Methylmalonic acidemia is usually caused by a deficiency of the enzyme methylmalonyl-CoA mutase, a defect in the transport or synthesis of its cofactor; adenosyl-cobalamin, or a deficiency of the enzyme methylmalonyl-CoA epimerase.
Molecular genetic testing is a useful tool for confirmation of diagnosis and genetic counseling.
The aim of the work is to characterize the clinical, biochemical and molecular features in Egyptian children with methylmalonic acidemia.
This cross sectional study was conducted on 18 Egyptian patients of 16 families with isolated methylmalonic acidemia of both sexes and age ranging from one year to ten years with exclusion of cases of combined methylmalonic acidemia and malonic aciduria and combined methylmalonic acidemia and homocystinuria. The patients included in the study were subjected to comprehensive history taking including thorough clinical characterizations; biochemical characterizations included renal profile, serum ammonia and arterial blood gases (ABG) in between crises, estimation of serum methylmalonic acid level (16 out of 18 patients) and serum amylase done during crisis only. Visual evoked potentials were recorded in (12 out of 18 patients).
Molecular study was done to find the common mutations among Egyptian patients and to predict the possible genotype phenotype correlation (13 out of 18 patients). cDNA was amplified by PCR. Five sets of primers were designed for amplification of specific sites covering the entire length of cDNA of MUT gene.
In the view of demographic data of the studied patients, our results included 10 males and 8 females with more residencies in Cairo. Positive consanguinity was in 16 patients and positive family history was in only 5 patients.
The infantile phenotype of methylmalonic acidemia was the predominanat among the studied population.
Delayed motor milestones were present in 14 patients and delayed mental milestones were present in 7 patients and delayed language was present in 8 patients while convulsions were present in 4 patients.
Renal impairment in between crises (based on high serum creatinine) was present in 2 patients and pancreatitis during crisis was present in 1 patient.
The compliance with treatment was found in 14 patients.The natural protein intake was found to be one gram per kg per day in 5 patients and two gram per kg per day in 4 patients, the majority of patients (8) were taking natural protein on one and half gram protein per kg per day. High serum ammonia was present in 6 patients.
Metabolic acidosis in between crises was present in 10 patients.
Serum methylmalonic acid estimation ranged between 1.60μmol/l and 330.00μmol/l, and there was significant negative correlation between MMA level and mental and language development. We also found significant correlation between methyl malonic acid and renal impairment.
Out of (18) patients with methylmalonic acidemia, (12) patients underwent complete ophthalmic and electrophysiological examination (both pattern and flash visual evoked potentials). All cases showed normal ocular findings, normal optic disc and normal fundus picture. Abnormal VEP recordings (mainly PVEP) were found in (8) of these cases. These dysfunctional changes were in the form of conduction delay through one or both of the visual pathways.
There is significant correlation between methylmalonic acid and visual evoked potential abnormalities.
Seventeen different mutations in the MUT gene of thirteen Egyptian families with methylmalonic acidemia MUT type were reported and reviewed (13 mutations were identified in the coding region of the MUT gene and 4 mutations in untranslated regions UTR3~ of the MUT gene). Seven mutations were in exon 2, four in exon 13 and three in exon 3.
Eight patients showed pathogenic mutations. Seven mutations were reported previously and one novel mutation. Four patients had single nucleotide polymorphism (Non pathogenic mutations) and one patient (P4) showed no detected mutations. These mutations varied between missense, nonsense, deletion, synonymous and silent mutations.
Novel mutation (P 14) was homozygous missense mutation in exon (4) c.794A>G, p.His265Arg. The clinical phenotype of this patient was severe neonatal type.
Molecular analysis of MUT cDNA of our patients had revealed that there is a homozygous synonymous mutation c.636G>A (p.Lys212=) in exon 3 which was identified in 8 patients and considered as the most common mutation among Egyptian patients with methylmalonic acidemia.
The only recognized visual abnormality was the subclinical mild to moderate optic nerve dysfunction (delayed VEP implicit time).
These finding were highly suggestive that the pathophysiological changes of optic neuropathy precedes clinical signs of optic disc changes.
Exons 2, 13 and 3 were hot spot exons and have to be kept in mind for the molecular analysis of the MUT gene of methylmalonic acidemia in Egyptian patients.