Hao-Fountain Syndrome

Schaaf C, Sailer S. USP7-Related Hao-Fountain Syndrome. 2025 Dec 4. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 41343689.cxcx/

Excerpt

Clinical characteristics: USP7-related Hao-Fountain syndrome is characterized by developmental delay in 100% of individuals, although intellectual disability is variable, with up to 50% of affected individuals having intellect in the normal range. Muscular hypotonia is also common; this tends to improve over time, but some affected individuals develop hypertonia. About two thirds of affected individuals have an abnormal/unsteady gait and about one quarter have contractures, most commonly involving large joints and joints of the lower extremities. Neuropsychiatric features can include autism, attention-deficit/hyperactivity disorder (ADHD), and behavioral issues such as stubbornness and compulsivity. Feeding difficulties are common and can require special feeding techniques, including use of a feeding tube. Gastroesophageal reflux disease, dysphagia, and hyperphagia have also been reported. Eye and vision issues (hyperopia, strabismus, nystagmus) are seen in more than 50% of affected individuals. About half of affected individuals have impaired bone mineralization, which can lead to fractures. Findings in fewer than 50% of individuals include epilepsy, sleep disturbance, hypogonadism, scoliosis, and hearing loss.

Diagnosis/testing: The diagnosis of USP7-related Hao-Fountain syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in USP7 identified by molecular genetic testing.

Management: Treatment of manifestations: Feeding therapy for poor weight gain / dysphagia; gastrostomy tube placement may be required for persistent feeding issues; consultation with a dietician when hyperphagia and/or obesity is present; adequate intake of Ca2+ and vitamin D for reduced bone mineral density. Standard treatment for developmental delay / intellectual disability, epilepsy, gastroesophageal reflux disease, diarrhea, constipation, eye issues, sleep disturbance, cryptorchidism, micropenis, hypothyroidism, growth hormone deficiency, adrenal insufficiency, and hearing loss.

Surveillance: At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake; monitor for signs/symptoms of constipation and gastroesophageal reflux disease; monitor those with seizures; assess for new manifestations such as seizures, changes in tone, and gait abnormalities; monitor developmental progress and educational needs; monitor for scoliosis, contractures, mobility, and self-help skills; monitor for evidence of aspiration, respiratory insufficiency, and sleep disturbance (including for signs/symptoms of sleep apnea); monitor for signs and symptoms of puberty starting at about age seven years to the late teenage years. Annually, behavioral assessment for anxiety, ADHD, autism spectrum disorder, aggression, and self-injury; evaluate for hypothyroidism; audiology evaluation (in childhood). Assess bone mineral density every two years starting at age five years and then every three to five years in adulthood. Ophthalmology evaluation and endocrinologic tests for adrenal insufficiency as clinically indicated.

Genetic counseling: USP7-related Hao-Fountain syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with USP7-related Hao-Fountain syndrome inherited a pathogenic variant from a parent. Each child of an individual with USP7-related Hao-Fountain syndrome has a 50% chance of inheriting the pathogenic variant. Once the USP7 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Korchak EJ, Sharafi M, Jaen Maisonet I, Salazar-Chaparro A, Semenova IV, Khan H, O'Neil AL, Caro P, Schaaf CP, Buhrlage SJ, Bezsonova I. Functional spectrum of USP7 pathogenic variants in Hao-Fountain syndrome: Insights into the enzyme's activity, stability, and allosteric modulation. Proc Natl Acad Sci U S A. 2025 Sep 30;122(39):e2510252122. doi: 10.1073/pnas.2510252122. Epub 2025 Sep 22. PMID: 40982686; PMCID: PMC12501124.

Abstract

Hao-Fountain syndrome is a rare neurodevelopmental disorder caused by mutations in the deubiquitinating enzyme Ubiquitin-Specific Protease 7 (USP7). Due to the novelty of the disease and its poorly understood molecular mechanisms, treatments for the syndrome are currently lacking. This study examines the effects of 11 patient-derived variants located within the catalytic domain of USP7, focusing on their impact on the enzyme's activity, thermodynamic stability, and substrate recognition. Our findings reveal a spectrum of functional consequences, ranging from complete inactivation to hyperactivation of USP7. Notably, we identify a specific subset of pathogenic variants whose catalytic activity can be significantly boosted using an allosteric activator, MS-8. These results provide insight into USP7 malfunction in Hao-Fountain syndrome-linked variants and pave the way for improved prognostic approaches and targeted treatments in the future.

Wimmer MC, Brennenstuhl H, Hirsch S, Dötsch L, Unser S, Caro P, Schaaf CP. Hao-Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum. Clin Genet. 2024 May;105(5):499-509. doi: 10.1111/cge.14480. Epub 2024 Jan 14. PMID: 38221796.

Abstract

Hao-Fountain syndrome (HAFOUS, OMIM: #616863) is a neurodevelopmental disorder caused by pathogenic variants in the gene USP7 coding for USP7, a protein involved in several crucial cellular homeostatic mechanisms and the recently described MUST complex. The phenotype of HAFOUS is insufficiently understood, yet there is a great need to better understand the spectrum of disease, genotype-phenotype correlations, and disease trajectories. We now present a larger cohort of 32 additional individuals and provide further clinical information about six previously reported individuals. A questionnaire-based study was performed to characterize the phenotype of Hao-Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders. In addition to confirming previously described features, we report hyperphagia and increased body weight in a subset of individuals. HAFOUS patients present an increased rate of birth complications, congenital anomalies, and abnormal pain thresholds. Speech impairment emerges as a potential hallmark of Hao-Fountain syndrome. Cognitive testing reports reveal borderline intellectual functioning on average, although some individuals score in the range of intellectual disability. Finally, we created a syndrome-specific severity score. This score neither indicates a sex- nor age-specific difference of clinical severity, yet highlights a more severe outcome when amino acid changes colocalize to the catalytic domain of the USP7 protein.

Rafeienejad F, Keyhani E, Akbarfahimi N, Nouri N. Neurodevelopmental disorder: Hao-Fountain syndrome with USP7 mutation-a case report. J Med Case Rep. 2025 Jul 24;19(1):363. doi: 10.1186/s13256-025-05403-y. PMID: 40707997; PMCID: PMC12291276.

Abstract

Background: Hao-Fountain syndrome (HAFOUS) is a rare neurodevelopmental disorder manifesting as several known symptoms, including speech and language delay, behavioral abnormalities, and intellectual disability. This rare condition is usually diagnosed by heterozygous deletion or mutation in the ubiquitin-specific protease 7 gene in conjunction with phenotype features.

Case presentation: We report the case of a 5-year-old Persian girl with this rare syndrome. The process of diagnosis, from perinatal examinations to the latest laboratory and clinical tests, is described for the first time in Iran.

Conclusion: Reporting all the symptoms of such a rare genetic case in detail emphasizes the importance of interdisciplinary teamwork and the necessity of raising awareness among therapists about probable upcoming problems; sharing such evident information with parents would help them manage the complexity of raising children with rare syndromes.

TUBGCP6 mutations

Inspired by a patient

Sengillo JD, Ashkenazy N, Shoji MK, Iyer P, Robles-Holmes HK, Lopez A, Yannuzzi NA, Negron CI, Berrocal AM. Familial Exudative Vitreoretinopathy-Like Phenotype in a Patient With Microcephaly and TUBGCP6 Mutations. J Vitreoretin Dis. 2023 Apr 10;7(4):344-347. doi: 10.1177/24741264231167236. PMID: 37927319; PMCID: PMC10621710.

Abstract

Purpose: To describe a case of microcephaly, unilateral retinal fold, and familial exudative vitreoretinopathy (FEVR)-like phenotype in the context of 2 TUBGCP6 variants. Methods: A case and its findings were analyzed. Results: A 4-month-old boy with no family history of eye disease presented by referral for management of presumed persistent fetal vasculature in the left eye. An external examination showed microcephaly. The patient grimaced to light in both eyes, and the anterior segments were unremarkable. On dilated fundus examination, diffuse chorioretinal atrophy was present bilaterally. In the left eye, a retinal fold emanated from the optic nerve head. There was early termination of retinal vasculature, especially in zone 3 in the left eye, resembling a FEVR-like phenotype. Panel-based genetic testing was performed and found 2 mutations in TUBGCP6. Conclusions: Microcephaly, chorioretinopathy, and retinal folds may be associated with TUBGCP6 mutations and masquerade as PFV.

Shurygina MF, Simonett JM, Parker MA, Mitchell A, Grigorian F, Lifton J, Nagiel A, Shpak AA, Dadali EL, Mishina IA, Weleber RG, Yang P, Pennesi ME. Genotype Phenotype Correlation and Variability in Microcephaly Associated With Chorioretinopathy or Familial Exudative Vitreoretinopathy. Invest Ophthalmol Vis Sci. 2020 Nov 2;61(13):2. doi: 10.1167/iovs.61.13.2. PMID: 33137195; PMCID: PMC7645200.

Abstract

Purpose: The purpose of this study was to analyze the natural history and phenotypic overlap of patients with microcephaly and a chorioretinopathy or familial exudative vitreoretinopathy (FEVR) ocular phenotype caused by mutations in KIF11, TUBGCP4, or TUBGCP6.

Methods: Patients diagnosed with congenital microcephaly and chorioretinopathy or FEVR were included. Molecular investigations consisted of targeted genetic sequencing. Data from medical records, ophthalmologic examination and imaging, electroretinography, and visual fields were analyzed for systemic and ophthalmic features and evidence of posterior segment disease progression.

Results: Twelve patients from 9 families were included and had a median of 8 years of follow-up. Nine patients had KIF11 variants, two had heterozygous TUBGCP6 variants, and one had heterozygous variants in TUBGCP4. All patients had reduced visual function and multiple individuals and families showed features of both chorioretinopathy and FEVR. Progression of posterior segment disease was highly variable, with some degree of increased atrophy of the macula or peripheral retina or increased vitreoretinal traction observed in 9 of 12 patients.

Conclusions: Microcephaly due to mutations in KIF11, TUBGCP4, or TUBGCP6 can be associated with retinal disease on a spectrum from chorioretinal atrophy to FEVR-like posterior segment changes. Visually significant disease progression can occur and patients should be monitored closely by a team experienced in ophthalmic genetics.

Hull S, Arno G, Ostergaard P, Pontikos N, Robson AG, Webster AR, Hogg CR, Wright GA, Henderson RHH, Martin CA, Jackson AP, Mansour S, Moore AT, Michaelides M. Clinical and Molecular Characterization of Familial Exudative Vitreoretinopathy Associated With Microcephaly. Am J Ophthalmol. 2019 Nov;207:87-98. doi: 10.1016/j.ajo.2019.05.001. Epub 2019 May 8. PMID: 31077665.

Abstract

Purpose: Familial exudative vitreoretinopathy (FEVR) is a rare finding in patients with genetic forms of microcephaly. This study documents the detailed phenotype and expands the range of genetic heterogeneity.

Design: Retrospective case series.

Methods: Twelve patients (10 families) with a diagnosis of FEVR and microcephaly were ascertained from pediatric genetic eye clinics and underwent full clinical assessment including retinal imaging. Molecular investigations included candidate gene Sanger sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS).

Results: All patients had reduced vision and nystagmus. Six were legally blind. Two probands carried bi-allelic LRP5 variants, both presenting with bilateral retinal folds. A novel homozygous splice variant, and 2 missense variants were identified. Subsequent bone density measurement identified osteoporosis in one proband. Four families had heterozygous KIF11 variants. Two probands had a retinal fold in one eye and chorioretinal atrophy in the other; the other 2 had bilateral retinal folds. Four heterozygous variants were found, including 2 large deletions not identified on Sanger sequencing or WES. Finally, a family of 2 children with learning difficulties, abnormal peripheral retinal vasculogenesis, and rod-cone dystrophy were investigated. They were found to have bi-allelic splicing variants in TUBGCP6. Three families remain unsolved following WES and WGS.

Conclusions: Molecular diagnosis has been achieved in 7 of 10 families investigated, including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in 3 families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.

Epilepsy surgery

By the time Charlotte “Charli” Hilz’s family drove from Dallas to Austin, they had tried nearly everything they had been offered to control her seizures: Seven medications, dietary changes and steroids had failed. Some treatments helped briefly, while others brought difficult side effects. All the while, two-year-old Charli was losing abilities she had already developed.

Her parents knew the situation was worsening. What they did not have was a clear path forward.

“My trust began to waver,” says Charli’s father, Trevor Hilz. “But I also didn’t know where to go.”

A family connection led them to Dave Clarke, M.D., chief of the Comprehensive Pediatric Epilepsy Program within the neurology clinic at Dell Children’s, a clinical partnership with Dell Medical School that is now ranked No. 21 in the country. Within a week, they had made the trip to Austin and begun a new evaluation — one designed not simply to try another medication, but to understand why the treatments had failed and whether a more definitive option was possible.

“Our program is designed to engage closely with families and across our disciplines to get to the root of the problem,” says Clarke, professor of pediatrics and neurology at Dell Medical School at The University of Texas at Austin. “Highly trained epileptologists, neurosurgeons who are able to take on high-risk procedures if needed, neuropsychologists, social workers, advanced practice providers and nurses — we all collaborate with the child and family at the center. That’s what makes the difference here: We are both capable and willing to go the extra mile for each child.”

National recognition for Austin pediatric programs

Charli’s journey points to a larger shift in the Central Texas medical landscape. For years, families in Austin routinely traveled to Dallas, Houston and elsewhere for highly specialized pediatric care. Charli’s family came in the opposite direction, seeking capabilities that an emerging academic pediatric neuroscience program had assembled here.

Created in 2019, the program brought pediatric neurology, neurosurgery, neuropsychology, neuro-ophthalmology, rehabilitation and related specialties into a more integrated model. It earned its first national recognition from U.S. News & World Report three years later. By 2025, the program had reached No. 25 in the country for pediatric neurology and neurosurgery. Today, it is tied for No. 21, one of a handful of programs led by Dell Med faculty now climbing in national recognition.

“The power of academic medicine is that patient care, research and education continually strengthen one another,” says Claudia Lucchinetti, M.D., senior vice president for medical affairs and dean of Dell Medical School at The University of Texas at Austin. “The needs of patients shape research, new discoveries create better outcomes, and education prepares more physicians to deliver the most advanced care. At Dell Children’s, Dell Med faculty bring that model together with outstanding clinical teams and the broader capabilities of UT to take on complex cases and find a path forward when standard answers fall short.

“These rankings reflect what matters for children and families: deeper expertise, more options, and access to nationally recognized care here in Central Texas.”

Charli’s journey from uncertainty to recovery

Other leading pediatric epilepsy centers around the country have access to many of the same advanced tools. But what Charli and her family needed — and had not yet found — was a team of advanced specialists prepared to put them together around her particular case.

“When advanced specialists come together, we can look at complex cases from every angle,” says Adam Messer, president of Dell Children’s Medical Center. “This collaboration helps us understand each child’s unique needs so we can provide comprehensive care that supports the entire family.”

Charli’s epilepsy began in one area of the brain but spread so rapidly that it could resemble a different type of seizure disorder. At the same time, abnormal electrical activity was disrupting more than half of her sleep, interfering with her brain’s ability to rest, learn and develop. She was having as many as 20 seizures a day, struggling to walk and speak clearly, and losing the use of her left hand.

At Dell Children’s, the team began again with inpatient monitoring, capturing Charli’s seizures and studying the electrical activity in her brain. Advanced imaging helped narrow the suspected source. Epileptologists, neurosurgeons and neuropsychologists then used stereo-EEG, placing small electrodes in and around the target area to determine precisely where her seizures began and how closely that area bordered functions that needed to be preserved.

The evaluation located a small area of atypical cells near Charli’s sensory cortex. The target was so tightly surrounded by functional tissue that conventional surgical removal could have caused harm.

Instead, the team guided a needle-sized probe between two folds of her brain and used laser energy to deactivate the cells driving the seizures while protecting the surrounding tissue.

Today, Charli is six years old and remains seizure-free. Her overnight epileptic episodes have largely disappeared. She is using both sides of her body more fully, taking fewer medications and rapidly regaining function her family once feared had been permanently lost.

“For the first time, we felt heard,” says Charli’s mother, Mackenzie Hilz. “Dr. Clarke believed us. He looked at her and us and said, ‘I have a plan.’ We hadn’t heard that from anyone before. We took the leap, and it saved her life.”

https://news.utexas.edu/2026/09/17/academic-medicine-raises-the-bar-for-pediatric-neuroscience-care-in-austin/

Diazepam Intensol shortage

 It seems there is a nationwide shortage of  inexpensive but effective Diazepam Intensol, forcing obscenely expensive Valtoco to be prescribed in yet more obscenely expensive 5 packs.

Great experiments 5

Courtesy of a colleague

Hot air? BMJ. 2001 Dec 22;323(7327):1449. PMCID: PMC1121900.

“It all started with an enquiry from a nurse,” Dr Karl Kruszelnicki told listeners to his science phone-in show on the Triple J radio station in Brisbane. “She wanted to know whether she was contaminating the operating theatre she worked in by quietly farting in the sterile environment during operations, and I realised that I didn't know. But I was determined to find out.”

Dr Kruszelnicki then described the method by which he had established whether human flatus was germ-laden, or merely malodorous. “I contacted Luke Tennent, a microbiologist in Canberra, and together we devised an experiment. He asked a colleague to break wind directly onto two Petri dishes from a distance of 5 centimetres, first fully clothed, then with his trousers down. Then he observed what happened. Overnight, the second Petri dish sprouted visible lumps of two types of bacteria that are usually found only in the gut and on the skin. But the flatus which had passed through clothing caused no bacteria to sprout, which suggests that clothing acts as a filter.

“Our deduction is that the enteric zone in the second Petri dish was caused by the flatus itself, and the splatter ring around that was caused by the sheer velocity of the fart, which blew skin bacteria from the cheeks and blasted it onto the dish. It seems, therefore, that flatus can cause infection if the emitter is naked, but not if he or she is clothed. But the results of the experiment should not be considered alarming, because neither type of bacterium is harmful. In fact, they're similar to the ‘friendly’ bacteria found in yoghurt.

“Our final conclusion? Don't fart naked near food. All right, it's not rocket science. But then again, maybe it is?”

Levacetylleucine for treatment of Niemann-Pick disease type C 2

Davis LC, Annaert W, Braine R, Churchill GC, Factor M, Fields T, Patterson M, Platt F, Shepherd D, Strupp M, Galione A. N-acetyl-L-leucine normalizes Transcription Factor EB activity by stereospecific bidirectional modulation in a HeLa cell model of Niemann-Pick disease type C. PLoS One. 2026 Jul 17;21(7):e0353834. doi: 10.1371/journal.pone.0353834. PMID: 42467639; PMCID: PMC13378962.

Abstract

Levacetylleucine (Aqneursa™), an acetylated derivative and pro-drug of L-leucine, is the only FDA-approved monotherapy for Niemann-Pick disease type C (NPC). Its acetyl group enables transport via monocarboxylate transporters, supporting blood-brain barrier penetration and efficient cellular uptake. Inside cells, levacetylleucine is metabolised by acylases, generating elevated levels of L-leucine that enhance mitochondrial bioenergetics and is thought to ameliorate lysosomal dysfunction indirectly. Here, we describe a direct effect of levacetylleucine on lysosomal regulation through modulation of TFEB, the master transcription factor for lysosomal and autophagy genes. Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner. In wild-type HeLa cells, levacetylleucine promotes TFEB activation and nuclear localisation. However, in NPC1 disease models, where we show that TFEB is over-activated and enriched in the nucleus due to lysosomal stress, levacetylleucine reduces nuclear TFEB and restores a more normal cytoplasmic-to-nuclear balance. These effects occur at clinically relevant concentrations associated with lysosomal storage reduction. The effects of the drug are stereospecific: while the L-enantiomer is active, the D-enantiomer and racemate show no effect, revealing the antagonistic properties of the D-enantiomer. This bidirectional normalisation of TFEB activity highlights a direct mechanism through which levacetylleucine modulates lysosomal and autophagic pathways in the HeLa cell model, giving mechanistic insight into its therapeutic potential in NPC, and also across diverse neurological and neurodevelopmental disorders.

Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannová S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K. Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024 Feb 1;390(5):421-431. doi: 10.1056/NEJMoa2310151. PMID: 38294974.

Abstract

Background: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C.

Methods: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo.

Results: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred.

Conclusions: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).

Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M. N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study. Trials. 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. PMID: 37248494; PMCID: PMC10226221.

Abstract

Background: Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC.

Methods: This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments.

Discussion: Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders.

Trial registrations: The trial (IB1001-301) has been registered at www.

Clinicaltrials: gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.

Keywords: Cerebellar ataxia; Lysosomal storage disease; N-acetyl-L-leucine; Niemann-Pick type C (NPC); Pharmaceutical intervention; Randomized controlled trial; Symptomatic treatment.

Du K, Chen H, Pan Z, Zhao M, Cheng S, Luo Y, Zhang W, Li D. Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis. Elife. 2025 Apr 4;13:RP103137. doi: 10.7554/eLife.103137. PMID: 40184172; PMCID: PMC11970905.

Abstract

Niemann-Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.

Levacetylleucine for treatment of ataxia-telangiectasia

The U.S. Food and Drug Administration has approved Aqneursa (levacetylleucine) for oral suspension to treat ataxia in adults and pediatric patients with ataxia-telangiectasia weighing at least 15 kg (about 33 pounds). Aqneursa was previously approved in 2024 to treat the neurological manifestations of Niemann-Pick disease type C. Today’s approval makes Aqneursa the first treatment approved for ataxia in patients with ataxia-telangiectasia.

Condition

Ataxia-telangiectasia is a rare, inherited neurodegenerative disorder caused by mutations in the ATM gene. It primarily affects the nervous system, causing progressive loss of muscle control and coordination (ataxia) that typically begins in early childhood. The disease also causes small dilated blood vessels (telangiectasias), immune deficiencies, and an elevated risk of cancer. There is no cure for ataxia-telangiectasia, and treatment options for the neurological symptoms of the disease have been limited.

Data Supporting Aqneursa

The effectiveness of Aqneursa was evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study (NCT06673056) of 73 patients aged 4 years or older with a confirmed diagnosis of ataxia-telangiectasia. Patients were randomly assigned to receive Aqneursa followed by placebo, or placebo followed by Aqneursa, with each treatment period lasting 12 weeks. Of the 73 patients (26 adults and 47 pediatric patients), 38 were female and 35 were male. The median age at treatment initiation was 13 years (range: 4 to 50 years). A total of 70 patients (96%) completed the study.

Efficacy was assessed using the functional Scale for Assessment and Rating of Ataxia (fSARA), a modified clinical tool evaluating gait, sitting, stance, and speech disturbance, with scores ranging from 0 (best neurological status) to 16 (worst). When patients were taking Aqneursa, they scored better on the fSARA compared to when these patients were taking placebo and showed significant improvement in neurological function.

Safety Information

There are no contraindications for Aqneursa, although this drug may cause fetal harm based on data from animal studies. The most common adverse reactions in patients with ataxia-telangiectasia were fall, skin laceration, and urinary tract infection.

Aqneursa interacts with N-acetyl-DL-leucine and simultaneous use should be avoided. Patients receiving P-glycoprotein (P-gp) substrates should be monitored more frequently for related adverse reactions when used with Aqneursa.

Designation

Aqneursa received Orphan Drug designation and Priority Review for the ataxia-telangiectasia indication. Approval was granted to IntraBio Inc.

https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-therapy-treat-ataxia-patients-ataxia-telangiectasia-rare-genetic-disorder

Martakis K, Bremova-Ertl T, Bolton C, Foltan T, Del Mar Garcia Romero M, Gautschi M, Han V, Hahn A, Kolnikova M, Panagioti O, Perlman S, Prasad M, Schmahmann J, Skorvanek M, Thakur N, Thiel M, Hoche F. Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial. Lancet Neurol. 2026 Jul;25(7):633-644. doi: 10.1016/S1474-4422(26)00158-4. PMID: 42309084.

Abstract

Background: Ataxia-telangiectasia is a rare, autosomal recessive neurodegenerative disorder. Levacetylleucine (N-acetyl-L-leucine) has been shown to be efficacious for the treatment of neurological manifestations and to have a disease-modifying effect in lysosomal storage disorders such as Niemann-Pick disease type C. We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia.

Methods: In this phase 3, randomised, double-blind, placebo-controlled crossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA. Eligible patients aged 4 years or older with genetically confirmed ataxia-telangiectasia were randomly assigned (1:1) using interactive response technology to receive two or three times daily orally administered levacetylleucine or a matching placebo over two consecutive 12-week treatment periods (patients weighing 35 kg or more received 4 g per day of orally administered levacetylleucine or a matching placebo three times per day and patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day). All participants, investigators, and assessors were blinded to group assignment. The primary outcome was the mean change on the Scale for the Assessment and Rating of Ataxia (SARA), assessed at baseline and at the end of each 12-week treatment period of levacetylleucine or placebo. Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random. The trial is registered with ClinicalTrials.gov, NCT06673056, and CTIS, 2024-517706-29; the open-label extension phase is ongoing.

Findings: Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion. Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets. 38 (52%) of 73 patients were female and 35 (48%) were male; 55 (75%) of 73 patients were White. 47 (64%) of 73 were younger than 18 years and 26 (36%) were aged 18 years or older. The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001). 54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred.

Interpretation: Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favourable benefit-risk profile for the treatment of ataxia-telangiectasia. An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects.

Funding: IntraBio.