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ASH1L LONGITUDINAL CASE PROFILE
Report transcript + cDNA
Report protein consequencep.Arg2146*
Normalized MANE/map notationNM_018489.3:c.6436C>T · NP_060959.2:p.Arg2146*
A warm, determined preschool-age girl with a highly variable history across development, communication, growth, feeding, bowel function, movement, vision, sensory regulation, spells, sleep, temperature, and medication response
Chapter 02Development, neurologic events, and sleep
Developmental, expressive and receptive language, motor, behavioral-regulation, and sensory concerns contributed to her evaluation. Her family felt that speech lagged more than gross movement.
At approximately 31 months, a formal neurological examination recorded gestures and one- to three-word sentences with mildly reduced articulation. By approximately 33 months, her family estimated that she used about 200 words, with vocabulary continuing to expand. She could communicate meaningfully, although unfamiliar listeners sometimes had difficulty understanding her.
Her family has not described a major loss of acquired skills. Instead, access fluctuates: speech, coordination, engagement, and regulation may be readily available at one time and much harder to access at another. During later off-baseline periods, she could begin a day quietly, use little speech for several hours, move more rigidly, or become rougher and more dysregulated before returning toward herself.
She plays with other children and has repeatedly been described as affectionate and socially interactive. Her family reports that developmental pediatrics did not identify an autism concern at the time of that evaluation. No formal cognitive score has been reported.
Her family later reported that the new preschool plan would provide an early-childhood teacher on each day she attended. Earlier school material described weekly early-childhood support and approximately monthly occupational, physical, and speech-language therapy, so the implemented frequency may have changed during the school year. Across settings, goals included initiating and responding with words, joint attention, reciprocal play with prompting, communication, motor planning, sensory regulation, safety awareness, and recognizing when a behavior change may signal physical discomfort.
Later school reports documented continued gains: she used one- to two-word phrases with models, navigated the school environment well, and showed good motor planning during playground activity. She improved to alternating feet on stairs, while skipping or galloping remained asymmetric, with the right foot leading. Observations varied by discipline and setting; reassuring school function does not mean that home or episodic motor concerns were absent.
She remains verbal, social, and independently mobile, although gait and access to speech continue to fluctuate. She can dress herself and eats without a current swallowing-safety concern. Her bowel course and treatment are summarized below.
Her family observed tremor-like shaking from infancy. The early pattern consisted of daily, low-amplitude, rapid shaking of both arms, often most noticeable on waking, with the elbows and fingers flexed. Her walking was not interrupted by these events. Horizontal “no-no” head movements occurred approximately once or twice per week, sometimes after frustration or a loud sound, with rapid return to baseline.
One video appeared to the family to show head movement during sleep, but the reviewing neurologist thought she was awake with her eyes closed. The clinician considered the early tremor and head-shaking pattern reassuring and not typical of seizures. Her family reports that a prior approximately 30-minute EEG was normal.
Because the events were frequent and seizures can occur in people with ASH1L-related disorders, a four-hour video EEG was completed at approximately 31 months. It showed:
The family believed she appeared to sleep for approximately two hours, but the EEG did not document stage II sleep. That single recording was not a polysomnogram and does not show that she fails to reach stage II sleep in ordinary life. The mild slowing was abnormal but nonspecific. It does not establish epilepsy, a particular cause of brain dysfunction, or a chronic sleep-stage disorder.
The family provided a report summary of a later ambulatory video EEG lasting 43 hours 31 minutes that captured N1, N2, N3, and REM sleep. In that summary, no seizures or interictal epileptiform activity were identified. Two possible blank-stare events had no electrographic seizure correlate, and the ECG channel showed no significant change. A subsequent sleep-clinic note summarized the posterior background as 4–5 Hz, compared with 6–7 Hz on the earlier study. The slower background description remains nonspecific. She has no confirmed epilepsy diagnosis and has not been treated with an antiseizure medication.
The family also describes brief episodes that differ from the early tremor. During these, she may become still or appear to freeze for approximately 30 seconds to two minutes, sometimes covering her ears or eyes, closing her eyes, rocking, or remaining partly responsive. She may look frightened or briefly confused but generally returns quickly to baseline.
During one episode at approximately 35 months, she sat in a corner with her eyes closed, covered her ears, and rocked. She remained purposeful and verbal enough to ask to be left alone, illustrating that at least some of these episodes include partial responsiveness.
At other times, her family has observed fixed staring with her head held to one side. This has not been formally classified and cannot be assumed to be the same event as either the sensory shutdowns or the pain-associated breath and limp episodes.
These episodes have not been captured with a confirmed electrographic seizure. Partial responsiveness and an association with sound or overwhelm have sometimes suggested a sensory shutdown to the family, but no clinical evaluation has assigned them a definitive sensory, seizure, cardiac, or autonomic classification.
Beginning at approximately 33 months, her family observed a separate group of events involving an inability or delay in initiating a cry or breath, altered color, limpness, stiffness, eye movement, sweating, or altered awareness. By the later sleep evaluation, family tracking and the clinic history described approximately eleven events in this broad category, although not every event was medically witnessed or described in equal detail.
The better-characterized sequence includes:
At the later sleep evaluation, the caregiver described pauses in breathing with stiffening or body contortion and fatigue afterward. This was reported history rather than an event observed during the visit.
Some events followed pain or crying, while others occurred during periods of gastrointestinal difficulty, waking, or temperature change. Recovery was usually rapid, although sleep sometimes followed. Clinically, the events remain unclassified. Features overlap with breath-holding, syncope, reflex-anoxic events, seizure-like activity, and cardiac or autonomic phenomena, but none of those explanations has been confirmed.
During the first hand-foot-and-mouth illness period, the family also observed a temporary one-sided mouth droop. It improved, and a later formal neurological examination found symmetric facial movement.
Her family reported a bedtime near 8:30 p.m., although she could remain awake until approximately 11:30 p.m. Once asleep, she usually slept through the night and woke near 7 a.m. She did not routinely nap on preschool days but sometimes fell asleep on the couch at home. Naps could improve regulation, while late-evening bursts of energy also occurred.
She occasionally sleeps with her mouth open. Her family has also observed brief soft cries from sleep lasting approximately 30–60 seconds, with little initial response to voice or touch followed by spontaneous self-soothing. After some waking periods, they have noticed head touching, shivering, cold complaints, unusual eye behavior, or a slow return to full engagement.
Sweating during naps has been recurrent, including one episode in which one side of her body was described as soaked. No polysomnogram has been completed, and no sleep disorder has been diagnosed.
At a later sleep-medicine visit, the family described sleep-onset latency of up to about three hours, restless light sleep with frequent movement and marked night sweating, and a tendency to end the night in a parent’s bed. When not awakened early, she often slept from roughly 11 p.m. to 9 a.m. Naps were uncommon, excessive daytime sleepiness was not reported, and intermittent mouth breathing or snoring was not loud or nightly; no witnessed apneas were reported.
The clinician assessed delayed sleep onset, restlessness, and reduced total sleep, considering neurodevelopmental and gastrointestinal contributors as well as possible iron deficiency. A later bedtime with less time in bed and a reward-based plan for remaining out of the parents’ room were discussed. The family later reported follow-up values of serum iron 139 µg/dL and ferritin 17 ng/mL. These reported values do not by themselves establish the cause of her sleep difficulty.
On examination at that visit, the nares were patent, tonsils small, heart rhythm regular without a murmur, lungs clear, abdomen soft and nontender, and tone, strength, coordination, reflexes, and gait documented as normal. This was a reassuring snapshot during one visit and does not erase the longitudinal variability described elsewhere.