A team of international scientists has identified a previously unrecognized form of diabetes affecting newborns, expanding current understanding of neonatal metabolic diseases. This rare condition, caused by specific biallelic mutations in the TMEM167A gene, disrupts the function of insulin-producing cells and is associated with early-onset diabetes along with neurological features such as microcephaly and epilepsy. The findings were published in The Journal of Clinical Investigation and are based on detailed genetic and cellular studies.
The study was supported by NIHR (National Institute for Health and Care Research). NIHR is the UK government's major funder of health and social care research.
Neonatal diabetes mellitus (NDM) 1 is a rare form of diabetes that manifests before six months of age and is caused primarily by single-gene mutations that impair insulin production or pancreatic development. It differs from more common forms of diabetes (like type 1 and type 2) both in timing and genetic origin. NDM can be permanent, requiring lifelong insulin therapy, or transient, resolving in infancy but sometimes recurring later in life.
In the recent study 2, researchers used whole-genome sequencing to analyse infants with neonatal diabetes accompanied by severe neurological symptoms (epilepsy and microcephaly). Six children from different families shared recessive mutations in the TMEM167A gene, suggesting a single genetic cause linking both metabolic and neurological dysfunction.
The gene TMEM167A had not previously been linked to neonatal diabetes, making this a newly recognized genetic etiology within the broader category of monogenic diabetes.
Pancreatic beta cells are responsible for producing insulin, the hormone that regulates blood glucose. The TMEM167A gene appears to play a crucial role in protein trafficking within cells, particularly in the endoplasmic reticulum (ER) to Golgi apparatus pathway – a process essential for the proper folding and secretion of proinsulin.
When TMEM167A is mutated:
Insulin-producing cells fail to traffic and secrete insulin correctly.
ER stress increases, leading to beta-cell dysfunction and death.
Blood glucose rises due to insufficient insulin, resulting in hyperglycemia and diabetes in the neonatal period.
The infants in the study shared several defining clinical characteristics:
Onset of diabetes within the first months of life, typically before six months old.
Severe hyperglycemia requiring early medical treatment.
Neurological abnormalities, including microcephaly (smaller than expected head size) and epilepsy, suggesting that TMEM167A also plays a role in neuron development and function.
The combination of metabolic and neurological symptoms is now described as part of a syndrome involving TMEM167A dysfunction, distinct from previously known forms of neonatal diabetes.
Identification of TMEM167A mutations informs precise genetic diagnosis for infants presenting with extremely early-onset diabetes.
Genetic testing panels for neonatal diabetes may now include TMEM167A to ensure early and accurate diagnosis.
Infants with this gene mutation often require insulin therapy from diagnosis due to insufficient endogenous production of insulin.
Neurological symptoms warrant multidisciplinary care, including pediatric neurology and developmental support.
This discovery has broader relevance beyond this rare condition:
It clarifies biological mechanisms of insulin production and beta-cell survival.
By elucidating pathways of beta-cell dysfunction, the findings may inform research on other forms of diabetes, including more common types.
The use of cutting-edge DNA sequencing and stem-cell models illustrates how genetic research can illuminate mechanisms underpinning rare diseases.
A rare form of neonatal diabetes caused by TMEM167A gene mutations has been identified in infants.
This form is associated with diabetes onset early in life, often before six months.
It also includes neurological features such as microcephaly and epilepsy.
The TMEM167A gene appears essential for proper insulin secretion and neuron development.
References
Lemelman, Michelle Blanco, Lisa Letourneau, and Siri Atma W. Greeley. 2018. “Neonatal Diabetes Mellitus: An Update on Diagnosis and Management.” Clinics in Perinatology 45, no. 1 (December 16): 41–59. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928785/.
Virgilio, Enrico, Sylvia Tielens, Georgia Bonfield, Fang-Shin Nian, Toshiaki Sawatani, Chiara Vinci, Molly Govier, Hossam Montaser, Romane Lartigue, Anoop Arunagiri, Alexandrine Liboz, Flavia Natividade Da Silva, Maria Lytrivi, Theodora Papadopoulou, Matthew N. Wakeling, James Russ-Silsby, Pamela Bowman, Matthew B. Johnson, Thomas W. Laver, Anthony Piron, Xiaoyan Yi, Federica Fantuzzi, Sirine Hendrickx, Mariana Igoillo-Esteve, Bruno J. Santacreu, Jananie Suntharesan, Radha Ghildiyal, Darshan Hegde, Nikhil Shah, Sezer Acar, Beyhan Özkaya Dönmez, Behzat Özkan, Fauzia Mohsin, Iman M. Talaat, Mohamed Tarek Abbas, Omar Tarek Abbas, Hamed Ali Alghamdi, Nurgun Kandemir, Sarah E. Flanagan, Raphael Scharfmann, Peter Arvan, Matthieu Raoux, Laurent Nguyen, Andrew T. Hattersley, Miriam Cnop, and Elisa De Franco. 2025. “Recessive TMEM167A Variants Cause Neonatal Diabetes, Microcephaly, and Epilepsy Syndrome.” The Journal of Clinical Investigation 135, no. 22 (November 17): e195756. https://doi.org/10.1172/JCI195756
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