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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 03Feeding, gastrointestinal history, and ENT/imaging
In addition to the early suck and dependence on soft food, her family has described a high-arched palate, intermittent raspy voice, occasional mouth-open sleep, and difficulty grading a spoon accurately toward her mouth. Later chewing or picking at nails, toes, skin, and surrounding tissue has sometimes been intense; on one occasion she removed a toenail.
Later genetics reviews recorded no dental concern and no current feeding or swallowing problem, and her family does not recall notably delayed tooth eruption. No formal chewing disorder has been diagnosed.
Appetite and fullness signals can be difficult to interpret. At times her appetite improves after a bowel movement. At other times she refuses food in a way that appears sensory. Her appetite varies rather than showing consistent excessive hunger.
Her bowel history has changed markedly over time.
During the first two months, she stooled approximately every 48 hours. After the early illness and onset of large-volume spit-ups, she developed a long period of frequent loose stool—often five to seven times per day and sometimes described as greasy, floating, or strong smelling. Reflux-like large spit-ups, occasionally forceful or projectile, were also prominent in infancy.
Later testing was reassuring against several common explanations for chronic loose stool:
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| Test | Result | Clinical interpretation |
|---|---|---|
| Fecal elastase | >800 μg/g | Did not support pancreatic insufficiency |
| Fecal calprotectin | 22 μg/g | Did not show marked intestinal inflammation |
| 72-hour fecal fat | 0.4 g/24 hours | Did not support significant fat malabsorption |
| Bile acids | 3.5 μmol/L | Reported within the expected range |
PT/INR and vitamins A, D, and E were reported as normal, as was celiac screening. These results do not identify the cause of the earlier loose-stool pattern or the infant spit-ups.
At approximately 30 months, she developed the first of three illnesses identified as hand-foot-and-mouth disease. The first illness included fever and her first known acetaminophen exposure. Within the first hour, her family observed a perioral rash, eyelid puffiness, and an abrupt change in which she remained awake but appeared unusually disengaged or shut down. The acute change resolved. Acetaminophen is now listed in her clinical record because of rash.
During the same broader illness and medication window, her bowel pattern shifted dramatically from frequent loose stools to constipation. The family also observed the temporary facial asymmetry described above. The timing is important, but it does not prove that acetaminophen caused the altered state, facial change, or lasting bowel transition.
Two additional illnesses identified as hand-foot-and-mouth disease occurred at approximately 32 months and again just before 33 completed months. They were not accompanied by fever or acetaminophen exposure, cleared relatively quickly, and were followed by continued or worsening constipation. Her family reports that she has not had another fever since the first hand-foot-and-mouth illness described above, including during the two later hand-foot-and-mouth illnesses. This observed history does not show that she is unable to mount a fever.
By approximately 34 months, constipation required daily medication. Treatment began with approximately 10.5 mL of lactulose daily, later increasing to 12 mL, with 3.75 mg of senna added. Polyethylene glycol had provided limited benefit during an earlier stage. Even with treatment, her family documented days with no bowel movement, smear-only output, large hard Bristol type 1 stools, mucus or liquid passing around retained hard stool, alternating stool forms, and episodes of pain or vomiting. A bright-red posterior fissure and perianal swelling were observed.
At approximately 35 months, she was already taking daily lactulose and senna when the severity of her retention became unmistakable. A stool log had appeared encouraging only two days earlier, and she showed no obvious abdominal pain. An emergency examination found her active and well appearing, with a soft, nontender abdomen. Imaging nevertheless showed a large amount of stool throughout the colon and rectum, including a large rectal stool ball; her family recalls being told that the retained stool amounted to approximately two feet. A glycerin suppository produced only hard fragments, and follow-up imaging still showed moderate-to-large stool burden. For her, visible comfort, a reassuring abdominal examination, daily medication, and apparently encouraging stool output did not reliably mean that her bowel was empty.
A clinician then directed a two-part polyethylene-glycol cleanout. The first part used 2.5 capfuls in 16 ounces; she drank approximately 12 ounces and passed a large, predominantly liquid output. The second used 1.5 capfuls in 10 ounces, which she completed, followed by formed and then loose stool. The maintenance regimen was adjusted repeatedly. By approximately 36 months, it had reached lactulose 15 mL twice daily and senna 15 mg twice daily, with clinician-directed rescue using glycerin suppositories or saline enemas. These doses describe her historical medical course; they are not treatment advice.
The evening immediately before anorectal manometry and Sitz-marker ingestion, a 33 mL saline enema produced a bowel movement within approximately five minutes. The next day, anorectal manometry and the first portion of the Sitz-marker study were completed. Both studies therefore occurred after rectal rescue treatment and while she remained on an active daily bowel regimen, rather than at an untreated baseline. Reported manometry values included an anal-sphincter length of 3.5 cm, resting pressure of 65 mm Hg, a present rectoanal inhibitory reflex, squeeze pressure of 189 mm Hg, and no spasms or prolonged return to baseline. The intact reflex, resting pressure, and strong squeeze were reassuring. Because of her age, however, defecation dynamics and rectal sensation were not assessed; the study therefore did not evaluate every possible contributor to incomplete evacuation.
For the Sitz-marker study, she swallowed approximately 22–23 of 24 markers, and the first radiograph was obtained that day. Two markers reportedly remained on a later film, and a third film was obtained several days later. The low remaining marker count reflected transit during that particular testing period, but it did not explain why she continued to experience severe intermittent retention in daily life. No specific outlet or motility diagnosis was assigned.
The family also tried two informal blue-dye observations. During one period, a clear color change was not seen for approximately nine days; after a later increase in the bowel regimen, green stool appeared at approximately 35 hours. These were home observations, not standardized transit tests.
Through the following months, the prescribed regimen reached lactulose 15 mL twice daily and senna 15 mg twice daily, although later entries show that she did not consistently accept every dose. Recurrent retention included smear-only output and repeated 33 mL saline-enema rescue with Bristol type 1 stool in late winter and spring. One episode followed a suppository that produced only a small stool. Daily stooling still did not reliably indicate complete evacuation.
In early spring, the family log shows a change from a 15 mg senna chew to liquid senna; the liquid concentration, volume, and equivalent dose were not documented. During the ambulatory EEG, two days of accepting only sips or partial doses coincided with no true bowel movement and then smear-only output. After the leads were removed and medication was accepted, she passed a large stool. This chronology is important but does not prove that either the EEG setup or medication acceptance caused the stool change.
By later spring and summer, medication acceptance was a major part of the bowel course. Most morning entries through late summer marked lactulose and liquid senna as not taken or refused, with occasional missed evening doses. She continued to stool on many days but had recurrent stool-free and smear-only days. After mid-spring, the family log contains no further enema or suppository entry; this means none was recorded, not that none occurred. The later interval therefore reflects both persistent bowel variability and substantial medication-acceptance limitations, not documented failure of a consistently administered twice-daily regimen.
During one prolonged off-baseline period, family notes recorded rigid movement, marked dysregulation, and several hours with little speech alongside medication refusal, smear-only or absent stool, and later suppository or enema rescue. The co-occurrence does not establish that retention caused the functional change.
She has also vomited during car travel and, at times, shown very little outward distress afterward. This fits her broader pattern of inconsistent outward responses to pain and internal discomfort. No cyclic-vomiting, vestibular, or autonomic diagnosis has been made.
The dose strip includes every consecutive dated medication entry in this audited interval. Weight is shown only on the seven dates when the log records it. Stool descriptions, smears, suppositories, and Bristol types remain in the complete profile narrative; they are not converted into a severity score. The parallel timing does not establish causation.
Lactulose, mL Senna, mg
At approximately 29 months, brain MRI with and without contrast was normal intracranially for age. Midline structures, cerebral volume, myelination, morphology, pituitary appearance, and gray- and white-matter signal were age appropriate. There was no mass, hemorrhage, infarction, hydrocephalus, migration abnormality, abnormal enhancement, or other structural brain explanation for her developmental or movement history.
The MRI did show near-complete bilateral paranasal sinus mucosal thickening and opacification and a trace, likely postinflammatory left mastoid effusion. Her family did not recall obvious congestion, fever, ear pain, or drainage at the time. Neurology explained that these can be incidental findings in young children, are not fluid on or around the brain, and were not shown to be specifically related to ASH1L.
The post-contrast portion was limited to an axial T1 sequence despite repeated attempts to re-sedate her. The documented medication sequence included intranasal midazolam 2 mg, intranasal dexmedetomidine 42 micrograms, and two intravenous midazolam doses of 0.5 mg each. Sedation remained unexpectedly inadequate. A diagnostic MRI report was issued despite the limited post-contrast portion, and no acute procedural complication was recorded. Her family reports that she remained awake or active until late that evening and that future sedated procedures were flagged for planning under general anesthesia.
Dexmedetomidine is listed in her clinical record as having the “opposite effect.” This was one unusually difficult sedation episode. It does not prove a generalized medication resistance, an allergy to anesthesia, a receptor-level mechanism, or an ASH1L-wide sedation pattern.
Formal audiology several days after the MRI found:
Some tone responses may have been above true threshold because her conditioned response slowed, and headphones were not attempted. The test was not ear-specific pure-tone audiometry, but hearing was considered adequate for speech and language access. Monitoring was advised. No recurrent ear-infection history was reported at that time.
At approximately 35 months, an emergency clinician described the left eardrum as red but did not diagnose acute otitis media or prescribe antibiotics. The family later reported a clear ENT examination. At other times, they have observed clear drainage from the left nostril, ear pressing, apparent nose discomfort on waking, occasional mouth-open sleep, intermittently “wet”-sounding breathing, and a raspy voice. No chronic ear, sinus, airway, or voice diagnosis has been established.
Displayed scale: 23–24 lb