The patient is a 3-year-old male born to a 34-year-old Caucasian mother and a 56-year-old Pakistani father. He has four sisters—ages 3, 10, 12, and 16—all of whom are in good health. There is no family history of consanguinity, psychiatric disorders, or autism.
Prenatal ultrasound examinations revealed a varicose vein in his umbilical cord and concern for possible intrauterine growth retardation for which labor was induced at 36 weeks gestation. His birth weigh was 1,960 g (between the 10th and 25th centile). No dysmorphic features were noted and he was discharged to home on day 4 of life.
Although the majority of his gross motor developmental milestones were normal—including crawling at 6–8 months and walking at 13–14 months—he was unable to sit without support until almost a year of age. This prompted referral to an early childhood intervention program through which he received physical, occupational, and speech therapy starting at 11 months of age. His fine motor development was delayed with development of a pincer grasp occurring at 2.5 years of age. He continues to prefer to use a raking motion when picking up small objects and has difficulty with zippers, buttons, and scissors. His language development was similarly delayed with his first word being said at 2–2.5 years of age. He does not speak in full sentences but does use short two to three word phrases. There has been no evidence of regression.
He was evaluated by his local school district at 2 years, 8 months of age using the Childhood Autism Rating Scale (CARS), the Autism Behavior Checklist Record (ABC), and the Gilliam Autism Rating Scale and the Behavior Assessment System for Children, Second Edition (BASC-2) and was felt to demonstrate characteristics consistent with a diagnosis of Pervasive Developmental Disorder, Not Otherwise Specified (PDD-NOS).
At 3 years, 2 months of age he was evaluated in a neuropsychiatric clinic where his score on the Modified Checklist for Autism in Toddlers was suggestive of an autism spectrum disorder and he was diagnosed with PDD-NOS.
He was then referred to the Clinic for Autistic Spectrum Disorders at Texas Children’s Hospital where an evaluation at 3 years, 6 months of age confirmed the diagnosis of PDD-NOS. During this evaluation, he was noted to have impairments in communication and social interactions—including lack of spontaneous make-believe play, poor eye contact, failure to develop peer relationships appropriate to developmental level, and a lack of social and emotional reciprocity—but he did not consistently demonstrate restricted repetitive and stereotyped patterns of behavior and activities.
On the Bayley Scales of Infant and Toddler Development-Third Edition, he scored well below age expected levels with composite cognitive (75) and social-emotional (75) domain scores within the borderline deficient range and composite language (65) and motor (64) scores within the deficient range. His scores on the Adaptive Behavior Scale were also well below age expected levels. The Gilliam Autism Rating Scale was completed by his parents. Scores indicated that the probability of Autism was “Very Likely”. His mother completed the Child Behavior Checklist and noted clinical elevations on measures of attention problems and aggressive behaviors, and borderline clinical elevations for emotional reactivity. With respect to DSM-Oriented Scales, clinical elevations were noted for Anxiety Problems and Attention-Deficit/Hyperactivity Disorder Problems.
His most recent physical examination was at 3 years, 9 months. His weight was 20.6 kg (97th centile), his height was 109.7 cm (98th centile), and his FOC was 51 cm (75th centile). No dysmorphic features were noted. His neurologic examination revealed slightly increased tone in his lower extremities bilaterally with two beats of clonus in his right lower extremity. He also demonstrated decreased ability to fully dorsiflex his bilateral lower extremities beyond 90°.
Fragile X testing and sequencing of MECP2 were normal. An unenhanced head CT was normal at 3 years of age but an MRI evaluation revealed multifocal scattered areas of gliosis and/or abnormal myelination in the bilateral cerebral white matter of unclear etiology.T1 hyperintense signal abnormalities in the globus pallidi were also noted with minimal to negligible hyperintense signal on the T2 weighted images and no corresponding signal abnormalities were identified on the gradient echo exam. Since T1-signal hyperintensities of the basal ganglia can be associated with manganese deposition caused by hepatic disease, liver enzymes were checked and the patient was found to have mildly elevated AST, GGT, and unconjugated bilirubin levels at 70 U/L (normal 20–60 U/L), 23 U/L (normal 6–19 U/L), and 1.0 (normal <1), respectively, with a normal ALT and alkaline phosphatase and mildly decrease in albumin at 3.4 g/dl (normal 3.7–5.5 g/dl). On a separate occasion, the patient’s ammonia was slightly elevated at 57 μmol/L (normal range 22–48 μmol/L) during an acute illness. Further metabolic evaluation, including measurements of orotic acid, lactate, urine organic acids, plasma amino acids, urine amino acids, and acylcarnitines failed to identify an underlying metabolic disorder.