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.