1 Diagnosis Very important Helps to decide the treatment Starting adequate management/treatment Establishing the health maintenance plan Helps to establish recurrence risk Predicting prognosis

2 DEVELOPMENTAL DISORDER/ MENTAL RETARDATION DYSMORPHICOTHER NON NON NEURO SIGNS DYSMORPHIC Diagnosedunknown Karyotype Diagnosis Cherry red spot Hepatomegaly Diagnosed

3 DEVELOPMENTAL DISORDER/ MENTAL RETARDATION DYSMORPHICOTHER NON NON NEURO SIGNS DYSMORPHIC MicrocephalicNormocephaic Macrocephalic Neuro signs +Neuro signs N CT/MRIMetabolic work upNon Specific MR DiagnoseDiagnoseFragile X syndrome

4 EPIDEMIOLOGY MCA/MR syndrome26% (Chromosome and others) Metabolic disorders6% CNS Developmental defects16% CP/Seizure/Hypotoni group34% Environmentally-Caused13% PureMR±Autism5% Wisconsin study 1978

5 Chromosomal (including fragile X)30% MCA syndrome4-5% Metabolic disorders3-5% CNS Developmental defects10-15% Aquired causes/ injuries15-20% Unknown cause25-38% McLaren & Bryson 1987

6 summary 5 major causes of DD/MR MCA syndrome CNS Malformation Metabolic disorder Aquired conditions “Pure/Non specific” MR

7 RATIONALE EVALUATION OF DD/MR Clinical Evaluation 3 generation pedigree Pre, peri, post natal history Physical examination (Minor anomaly) Neurological evaluation Assessment of behavioral phenotype

8 Laboratory testing CBC Blood sugar Serum calcium Serum inorganic phosphorus Creatinine in plasma & urine (Increased level on creatinine found in urine and plasma in X linked creatinine- transporter gene (SLC6A8) defect – mild MR, severe speech delay, hypotonia) Metabolic testing – as indicated by clinical examination –Urine ferric chloride test –Urine DPNH test –Amino acid profile in urine / plasma

9 Laboratory testing SPECT HMPAO/ ECD Karyotyping Fish analysis Fibroblast karyotype Fragile X in both male and female Neuroimaging Fundus examination

10 Laboratory testing Arginine:Glycine amidinotransferase deficiency: (Mild MR. Severe speech delay, with normal examination/OFC and blood creatinine levels. MRS disclosed the total absence of creatinine/phosphocreatinine peak in multiple brain areas Creatinine monohydrate oral administration restored brain creatinine levels along with improvement of the patient disability

11 X linked Mental retardation 5 – 14% of MR 130 X – Linked syndromes MRX – 75 gene loci Fragile X ¼ - 6,000 males Am J Med Genet 2000, 97 (3):1

12 Good indicators for subtelomeric defects Family history of MR Prenatal onset of growth retardation Post natal poor growth/over growth 2 or more facial dysmorphic features 1 or more non facial dysmorphic features and/or congenital abnormalities

13 Differential diagosis DD/MR Physical, neurological examination Normal findingabnormal finding Do Karyotyping/DNA fra(X) 47,xxy,fra (x)Normal results Idiopathic MR

14 DD/MR Physical, Neurological examination Abnormal finding with No major, minor anomaly Signs of metabolic disorderNo Signs of metabolic disorder Signs of storage disorder Signs of paroxysmal disorder Signs of metabolic disorders Micro/macro cephaly ± Sec. anomaly Spasticity seizures ± Sec. anomaly Do Appro. Biochemical Studies Do Appro. Biochemical studies Do imaging ± EEG Do imaging ± EEG Metabolic Hurler syndrome Zellweger ALD MenkesLissencephalyCBPS, HIE

15 DD/MR Physical, Neurological examination Abnormal finding with major, minor anomaly i.e MCA/MR Diag. Of MCA/MR Syndrome Signs of fragile X Signs of SLONo evident Diagnosis RTS,KBGDo DNA Fra (X) Appro. Biochemical studies Do Karyotyping Signs of micro deletion Fra (X) SLO9 P deletionDo HBR/ FISH Normal results PWS< WHS Subtelomeric Chromosome DiagnosisNormal results Idiopathic MCA/MR

16 RATIONALE EVALUATION OF DD/MR CONCLUSIONS Through physical examination + awareness of the existence of definite patterns of malformations Newer diagnostic techniquesDiagnosis