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Individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), often experience a higher prevalence of gastrointestinal (GI) symptoms but have complex medical and behavioral comorbidities that make diagnosis and treatment difficult. A multi‐stakeholder conference was convened to (a) determine patient and family experiences related to GI symptoms in NDDs, (b) review the clinicians' and researchers' perspectives, and (c) determine actionable steps for future research. The Consortium for Autism, Neurodevelopmental Disorders and Digestive Diseases (CANDID; www.candidgi.com) virtually over 2 days in 2022 and consisted of four key activities: (1) an electronic family survey to assess underlying NDDs and GI symptoms, (2) a session focused on family perspectives, (3) review current clinical care and research, and (4) discussion to identify key next steps. Survey results were obtained electronically via the REDCap platform, and descriptive statistics were generated. The sessions were recorded, and themes were identified. The pre‐conference survey ran for ~2 months and 739 families provided responses, with 634 completing all items. 83% had a child with an NDD under age 18, and most patients were White (85%) and non‐Hispanic (87%). Constipation (80%), GI reflux disease (51%), and bloating (49%) were the most frequently reported symptoms. Families gave unstructured feedback that the measures used in the surveys were often difficult to answer for patients with NDDs or who were nonspeaking. Family and clinical/scientific sessions identified several common themes, including (1) the need for less invasive diagnostic modalities, (2) the need to validate or adapt existing diagnostic measures (e.g., the Rome IV criteria) and outcome assessments, and (3) the need for enhanced attention to parent and caregiver input in treatment plans. Those providing care to children with NDDs, especially those with communication and cognitive challenges, should be aware of the differing needs in this community and consider family perspectives in managing, treating, and measuring GI issues. Future research should focus on adapting or creating diagnostic and research measures for those with NDDs, developing new diagnostic methods to account for diversity in neurodevelopment and communication, and improving methods for family and caregiver engagement in the care of GI disorders. Gastrointestinal (GI) problems are common comorbidities in those with neurodevelopmental disorders (NDDs). These GI conditions can compound problems in neurodevelopment, leading to behavioral and psychiatric challenges like aggression, self‐injury, anxiety, and withdrawn behavior.There is a dearth of data regarding the causes, course, diagnosis, and treatment of GI symptoms in this population. Gastrointestinal (GI) problems are common comorbidities in those with neurodevelopmental disorders (NDDs). These GI conditions can compound problems in neurodevelopment, leading to behavioral and psychiatric challenges like aggression, self‐injury, anxiety, and withdrawn behavior. There is a dearth of data regarding the causes, course, diagnosis, and treatment of GI symptoms in this population. A multidisciplinary Consortium for Autism, Neurodevelopmental Disorders and Digestive Diseases (CANDID) was formed to bring together key stakeholders to discuss GI conditions in those with NDDs and autism spectrum disorder.CANDID identified three key areas for future work: (1) adaptation of diagnostic and research measures for those with NDDs, (2) improved diagnostic methods for those with developmental or communication deficits, and (3) enhanced focus on family/caregiver input in planning for diagnosis and treatment. A multidisciplinary Consortium for Autism, Neurodevelopmental Disorders and Digestive Diseases (CANDID) was formed to bring together key stakeholders to discuss GI conditions in those with NDDs and autism spectrum disorder. CANDID identified three key areas for future work: (1) adaptation of diagnostic and research measures for those with NDDs, (2) improved diagnostic methods for those with developmental or communication deficits, and (3) enhanced focus on family/caregiver input in planning for diagnosis and treatment.

Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy. We identified 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state. SORD is an enzyme that converts sorbitol into fructose in the two-step polyol pathway previously implicated in diabetic neuropathy. In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol. Furthermore, the serum fasting sorbitol levels in patients were dramatically increased. In Drosophila, loss of SORDorthologs caused synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient-derived fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a novel and potentially treatable cause of neuropathy and may contribute to a better understanding of the pathophysiology of diabetes.

1Early in development, ascidian muscle cells generate spontaneous, long‐duration action potentials that are mediated by a high‐threshold, inactivating Ca2+current. This spontaneous activity is required for appropriate physiological development.2Mature muscle cells generate brief action potentials only in response to motor neuron input. The mature action potential is mediated by a high‐threshold sustained Ca2+current.3Action potentials recorded from these two stages were imposed as voltage‐clamp commands on cells of the same and different stages from which they were recorded. This strategy allowed us to study how immature and mature Ca2+currents are optimized to their particular functions.4Total Ca2+entry during an action potential did not change during development. The developmental increase in Ca2+current density exactly compensated for decreased spike duration. This compensation was a function purely of Ca2+current density, not of the transition from immature to mature Ca2+current types.5In immature cells, Ca2+entry was spread out over the entire waveform of spontaneous activity, including the interspike voltage trajectory. This almost continuous Ca2+entry may be important in triggering Ca2+‐dependent developmental programmes, and is a function of the slightly more negative voltage dependence of the immature Ca2+current.6In contrast, Ca2+entry in mature cells was confined to the action potential itself, because of the slightly more positive voltage dependence of the mature Ca2+current. This may be important in permitting rapid contraction‐relaxation cycles during larval swimming.7The inactivation of the immature Ca2+current serves to limit the frequency and burst duration of spontaneous activity. The sustained kinetics of the mature Ca2+current permit high‐frequency firing during larval swimming.

1In embryonic ascidian muscle, outward K+currents develop in two stages: the initial expression of a slowly activating, voltage‐gated K+current (IKv) near the time of neurulation is followed about 6 h later by a rapidly activating calcium‐activated K+current (IK(Ca)). During this 6 h interval, inward Ca2+currents (ICa) appear and the inward rectifier (IK(IR)), the sole resting conductance, is transiently downregulated. These events predict a period of spontaneous activity. The following experiments were designed to test this prediction and to examine the relevance of spontaneous activity for muscle cell development.2By recording activity in cell‐attached patches, we have found that muscle cells generate spontaneous action potentials during this 6 h window of time when IK(IR)is downregulated and outward K+currents are slow. Action potentials occur at a mean frequency of 13.9 min−1.3When activity is blocked by the transient application of the Ca2+channel blocker Cd2+, IK(Ca)fails to develop. This disruption is specific for IK(Ca): IK(IR)and ICadevelop normally in activity‐blocked cells. Application of Cd2+either before or after the window of activity has no effect.4The reappearance of IK(IR)and the development of IK(Ca)and the mature form of ICaare all prevented by transcription blockers, with a sensitive period corresponding to the period of activity.5These data show that, although the expression of three channel types depends on transcription during the period of spontaneous activity, only the development of IK(Ca)depends on activity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.