Evaluation & Testing Practice Activity

Niko Case Study

Patient Intake: Niko

Presenting Concerns
3 years, male Recently presented with his first grand mal seizure Parents also report that he has a history of staring spells for the past 6 months

Developmental History Developmentally delayed; Niko sat at 15 months, pulling to stand but not walking on his own Non-verbal, has some vocalizations Behavior is autistic-like and hyperactive. Past Medical History Increased drooling without problems swallowing Difficulty sleeping through the night Past Evaluations MRI and Magnetic Resonance Spectroscopy (MRS) of the brain were normal. EEG revealed generalized spikes Normal newborn screening Birth History Born at full term to a 28 year old G2P2 without complications Social History Lives at home with his mother, a school teacher and father, an insurance salesman Has one older brother, age 8 Family History Older brother has a history of speech delay until age 4 when he was discharged from speech therapy. Now in third grade
doing well in school Dad has a history of medically controlled hypertension Mother has migraines

Physical Exam Normal growth parameters, height and weight between 50-75%, OFC is 25% General exam reveals similar coloring to parents: light skin and hair, eyes are blue Mental status shows delayed child with poor attention and no speech Behavioral assessment notes a happy child with hyperactivity, hand flapping, and no eye contact Mild generalized hypotonia centrally with increased tone at ankles bilaterally and several beats of clonus. Coordination
shows tremulousness and jerking movements when reaching for objects

Published June 2013 NCHPEG All rights reserved

Differential Diagnosis
Smith-Lemli-Opitz syndrome
Clinical features: Characteristic facial features and minor anomalies, intellectual disability, short stature with failure to thrive, microcephaly, hypotonia, and motor delay. Seizures have been described in SLO, but are not common. Genetics: Autosomal recessive inheritance. Typically due to sequence changes in DHCR7 gene, which interrupts cholesterol biosynthesis from 7-dehydrocholesterol (7-DHC). Diagnosis: Established with elevated serum concentration of 7-DHC. Serum cholesterol levels may be reduced but are not diagnostic. Sequencing or mutation analysis of the DHCR7 gene is second-tier testing for the purposes of confirmation or reproductive planning.

Phenylketonuria (PKU)
Clinical features: Motor delay, hypopigmented skin and hair, hyperactivity, and intellectual disability. Seizures can occur in older children with inadequate treatment. Genetics: Autosomal recessive inheritance. Typically due to sequence changes in PAH gene. Less commonly due to gene deletions. Mutations result in a deficiency of phenylalanine hydroxylase and disrupt metabolism of the dietary amino acid phenylalanine (Phe), causing a toxic build-up. Diagnosis: Persistently elevated plasma Phe concentration (higher than 120 mol/L) is diagnostic. Sequencing or deletion analysis of the PAH gene is second-tier testing for the purposes of confirmation or reproductive planning.

Angelman syndrome
Clinical features: Intellectual disability, speech impairment, motor delay and movement disorder, inappropriate happy affect, autistic-like behavior, hand-flapping, seizures, and microcephaly. Genetics: Usually occurs as a new variant and is not inherited. Associated with disruption of the maternal copy of the gene UBE3A, located within a critical region of chromosome 15. In unaffected individuals, the maternal copy of this region is methylated (imprinted) while the paternal copy is not. Affected individuals have only paternal, unmethylated contribu tions. Many causes + including microdeletion, paternal uniparental disomy* or imprinting defects . Less commonly associated with sequence changes in UBE3A. Diagnosis: Methylation analysis of the critical region 15q11.2-q13 identifies unbalanced parental contribution and is diagnostic in most individuals. Microdeletions can also be detected by fluorescent in situ hybridization (FISH) or chromosomal microarray (CMA). Testing reflexes to UBE3A sequence analysis when methylation studies are not informative.

Creatine transporter deficiency

Clinical features: Intellectual disability, motor delays, speech delay, autistic-like, behavior disorders, and seizures. Genetics: X-linked inheritance. Typically due to sequence variants in SLC6A8 gene, impairing uptake of creatine by sodium and chloride transport channels in fibroblasts. Rarely due to gene deletions. Diagnosis: When creatine/creatinine ratio is elevated, the condition is strongly suspected. Sequencing of SLC6A8 is confirmatory. Enzyme activity in cultured fibroblasts can be assessed when genetic test results are inconclusive.

Testing Options
Methylation analysis of a specific chromosome region Identifies regions of DNA that are normally or abnormally methylated. Sequencing of a specific gene Determines the exact sequence of nucleotide bases in a strand of DNA. Serum and urine amino acids Identifies some inborn errors of metabolism due to enzyme and transport molecule deficiencies Other specific metabolic/biochemical testing Identifies some inborn errors of metabolism due to enzyme and transport molecule deficiencies Chromosomal microarray analysis Detects microdeletions/duplications of submicroscopic chromosome regions (also called copy number variants). Some
arrays may also identify loss of heterozygosity and uniparental disomy.

Published June 2013 NCHPEG All rights reserved

Question 1: What unique features might help narrow the differential?

Question 2: What is the most likely diagnosis?

Question 3: What evidence suggests that diagnosis? What evidence led you away from the other diagnoses?

Question 4: Which of the tests listed above do you recommend?

Question 5: Results of the first analysis were normal. What is your next step?

Published June 2013 NCHPEG All rights reserved