Clinical Presentation and Family History
The subject is a 33-year-old man presenting with mild-to-moderate intellectual disabilities; the family has spent a lifetime on an odyssey to understand the subject’s condition and to collaborate with clinicians to develop a best treatment strategy. The subject has mild facial dysmorphology that includes large ears. He also has excessive drooling. He has scoliosis, gait disturbance, slender build, slender fingers, and a history of extensive tremors. He was born to a non-consanguineous family. He has a healthy and neurotypical younger male sibling. He presents with global developmental delays, attention deficit disorder, hyperactivity, impairment of fine and gross motor coordination, generalized hypotonia, and temper tantrums. Anxiety, impulsivity, and depression were also reported and he was diagnosed with anxiety and mood arousal regulation disorder in 2007. Neuropsychological evaluation was remarkable for poor attention span. Family history is noted for leukemia in his paternal grandfather and possibly autism in his father’s sister’s son. There is a history of autism spectrum disorder in both the paternal and maternal side of the family.
The proband was born first in birth order from an unremarkable and uncomplicated pregnancy, other than light spotting in the first trimester. He was born at full term via normal, spontaneous vaginal delivery with a birth weight of 8 lbs. 4 1/2 oz (95th percentile). There were no perinatal complications. The proband’s first febrile seizure was noted at 11-12 months of age. The seizure was mild and lasted ten minutes in duration. He then had multiple seizures after 17 months of age. Recurrent seizures consist of blank stares, and repetitive jerks of the head without dropping, that lasted a few seconds in duration. These episodes were very frequent and may occur 10 to 20 times over a period of thirty minutes. Ethosuximide was not effective in treating seizures and was replaced with valproic acid with an improved response noted.
He had a history of no expressive language and an attention deficit disorder. During an early clinic visit as a child, the boy was observed to be social but nonverbal. He had absent speech but could communicate using simple signing. EEG and CT scans were first conducted at one year of age and were both unremarkable. Thirty-two years ago, chromosomal studies were reported as unremarkable, although this would have been karyotype only.
At 3 years, 3 months of age, referral to medical genetics was made. The proband’s height, weight, and head circumference were at the 85th, 75th, and 45th percentile, respectively. The neurological exam showed hyperactivity, impairment of fine and gross motor coordination, and generalized hypotonia. Neuropsychological evaluation was remarkable for poor attention span and learning and intellectual disability. His expressive language was assessed as being less than an eight month level and his receptive language was at 2 to 2 ½ year level. A Test of Nonverbal Intelligence Test (TONI-4) was administered twice to assess abstract reasoning and problem solving, of which he scored 85 and 119, respectively on an index score of 100 and a standard deviation of 15. At the same time, cytogenetic evaluation was performed to rule out Angelman syndrome, (AS). Analyses indicated that the critical DNA region for AS had not been deleted; although it was noted that additional DNA markers were needed to completely rule out AS.
At four years of age, he had a weight, height, and head circumference of 50th, 90th, and 45th percentile, respectively. His weight percentile dropped from 85th to 50th, and to this day he is lean. He did not have expressive language and could only say “hi” or “bye.” The subject was able to follow one and two-step commands and had poor coordination. The proband was referred to a psycholinguistic evaluation and was diagnosed with Seizure disorder and Developmental Receptive and Expressive Language disorder. At six years of age, EEG was indicative of diffuse cerebral dysfunction, and consistent with a diagnosis of primary generalized epilepsy. He only developed limited spoken language despite receiving nonverbal cognitive scores in the average range of his age. Valproic acid was increased to 500 mg bid, from 125 mg bid and carnitine was recommended. By 10 years of age, the proband’s nonverbal mental age did not continue to maintain the same rate of change as his physical age, dropping to an IQ of 68, as measured by the Leiter-R. He also underwent back surgery that year for correction of severe kyphosis.
The next follow-up psychiatric visit was when the subject was 17 years of age. He was noted to be ambulatory with abnormal gait, dysarthric, with a continuance of tremors and seizures. Due to his significant hand tremors, he required assistance with his daily living routine. He did not exhibit self-injurious behavior and psychosis was not observed.
The proband was seen again for neuropsychological evaluation at 21 years of age. His general intelligence function was assessed with the Stanford Binet Intelligence Scales, Fifth Edition. He obtained a Verbal IQ of 43 (<1st percentile), a Nonverbal IQ of 52 (<1st percentile), and a combined IQ of 45 (<1st percentile). This score placed him in the moderately delayed range of general intelligence function. His adaptive behavior was also estimated with the Vineland Adaptive Behavioral Scales, Second Edition, which placed him at an approximate age equivalent of 3 years 7 months. His adaptive skills, including communication, daily living skills, and socialization, were hindered in part by delays in communication skills and significant tremors.
In 2023, and at 31 years of age, he returned again to the George A. Jervis Clinic at the New York Institute for Basic Research, Staten Island, New York for an updated psychological and genetic evaluation. The proband continued to have extensive tremors which affected his daily functioning such as feeding himself. He also had choreoathetosis and possible dyskinesias. Ataxia was not noted. At the visit, Fragile X testing was reported as negative. Brain MRI was unattainable because of the steel rods placed following kyphosis correction surgery. The proband’s lipid panel was obtained (Table 1 ) and showed abnormally elevated levels of total cholesterol, triglycerides, LDL cholesterol, and low HDL cholesterol, but a normal BMI of 21.7 kg/m2. In 2023, additional lab testing did not find any abnormality with his oxysterol profile (see Table 2 ).Table S1 shows a comprehensive list of the current medications of the proband. Epilepsy is currently controlled with clonazepam.