For a tiny number of families, those first days in the maternity ward turn into a medical investigation. Doctors pick up sky-high blood sugar, seizures or an unusually small head size. Behind these clues, researchers are now tracing a single genetic fault that appears to knock out both the pancreas and the developing brain.
A rare form of diabetes that signals deeper trouble
Neonatal diabetes is diagnosed in the first six months of life and demands rapid treatment. Unlike type 1 or type 2 diabetes, this condition almost always has a genetic cause. In around 85% of known cases, a mutation interferes with insulin production or release.
For some infants, raised blood sugar is only part of the story. Doctors also detect severe neurological signs: early seizures, stunted head growth known as microcephaly, or clear structural changes on brain scans. When these features appear together, they can signal a rare syndrome previously tied to just two genes.
This condition is often grouped under the label MEDS syndrome. It combines three major features from birth:
- Neonatal diabetes
- Epilepsy or frequent seizures
- Abnormal brain development, often including microcephaly
Until recently, only mutations in two genes, IER3IP1 and YIPF5, were firmly linked to this pattern. Both are involved in how proteins are moved and processed inside cells, including insulin inside pancreatic beta cells.
A third genetic culprit: TMEM167A
In 2025, a European research team reported a third gene that fits the same pattern. They studied six children who all had neonatal diabetes, microcephaly and, in most cases, epilepsy. Genetic sequencing pointed to a recessive mutation in a little-known gene called TMEM167A.
TMEM167A mutations appear to act like a double hit: they damage the insulin-producing pancreas and the developing brain at the same time.
Recessive means that each child inherited one faulty copy of the gene from each parent, who were healthy carriers. None of the parents showed signs of diabetes or neurological disease, which made standard clinical clues almost invisible before genetic testing.
Where TMEM167A acts inside the body
The team then examined when and where TMEM167A is switched on during early development. They found strong activity in two organs at crucial growth stages: the pancreas and the brain.
➡️ Why overthinking is often linked to a strong sense of responsibility
➡️ This is why sitting still all day can feel more exhausting than moving
➡️ Gold and silver prices plunge sharply – biggest price crash since 1980
➡️ One simple gesture is enough as DJI launches a new drone that almost flies itself
➡️ “At 66, my balance improved with slower steps”: the reflex timing adjustment
In human foetal brain tissue, TMEM167A is particularly active in areas where new neurons are born, including the cerebral cortex (pallium) and deep structures called basal ganglia. Lab-grown “mini-brains”, known as cerebral organoids, showed the same pattern. The gene was far more active in neural stem cells than in mature neurons, hinting that it shapes early brain architecture.
The pattern in the pancreas mirrors this. During the first weeks of gestation, TMEM167A appears in almost all pancreatic cells: early progenitors and future hormone-producing cells, including beta cells that will eventually secrete insulin. It sits alongside classic insulin markers in embryonic tissue samples.
This shared expression profile helps explain why a single mutation can trigger both diabetes and major neurological disability from birth.
Inside the cell: a traffic jam with serious consequences
To go beyond genetic association, researchers recreated the mutation in human stem cells. They then coaxed these modified cells to develop into beta-like cells, similar to those found in a healthy pancreas.
Under the microscope, something striking appeared. The internal transport system of the cells was badly disrupted. The route between the endoplasmic reticulum (ER) and the Golgi apparatus — two key compartments that process and package proteins — was blocked or slowed.
This traffic route is vital for insulin. Beta cells first produce a precursor called proinsulin in the ER, which must travel to the Golgi to be trimmed and folded into functional insulin. With TMEM167A impaired, that journey breaks down.
When ER–Golgi transport falters, proinsulin cannot be properly processed, insulin output drops, and the cells come under intense stress.
The stressed beta-like cells showed higher rates of malfunction and early cell death. When the team transplanted them into mice, the cells failed to secrete insulin even when pushed with a glucose challenge. That failure matched the severe diabetes observed in affected babies.
Early hints of new therapies
Although a rare condition, TMEM167A-related neonatal diabetes opens a window on potential treatments. In the lab, scientists tested compounds designed to ease cellular stress and boost survival.
Two drugs drew attention:
- Exendin-4, a molecule related to GLP-1 drugs already used in some forms of diabetes
- Imeglimin, a compound studied for its effects on mitochondrial function and cellular metabolism
Both treatments helped reduce stress signals in the mutated beta-like cells and improved their survival over time. The cells still showed a fundamental transport defect, but the interventions kept more of them alive for longer.
Targeting cell stress and intracellular trafficking could one day benefit children whose diabetes stems from deep cellular faults rather than classic autoimmune attacks.
What this means for families and clinicians
For parents, the combination of newborn diabetes, seizures and developmental delay is devastating and confusing. This genetic work gives a clearer explanation for at least a subset of these cases and supports early genetic testing for babies presenting with this trio of symptoms.
For clinicians, TMEM167A offers another candidate in gene panels for neonatal diabetes and microcephaly. Knowing the exact mutation can guide management: it may prompt closer neurological follow-up, tailored seizure control, and discussion about experimental options in specialist centres.
| Feature | Classic type 1 diabetes | Neonatal diabetes linked to TMEM167A |
|---|---|---|
| Age at onset | Usually childhood or adolescence | First weeks or months of life |
| Main cause | Autoimmune destruction of beta cells | Inherited mutation affecting cell trafficking |
| Neurological involvement | Generally absent at onset | Frequent microcephaly and seizures |
| Treatment goal | Replace missing insulin | Manage diabetes and protect vulnerable cells |
Key terms that help make sense of the research
For readers less familiar with cell biology, a few definitions help clarify what is going on inside these damaged cells:
- Endoplasmic reticulum (ER): a network of membranes where many proteins, including proinsulin, are first made and folded.
- Golgi apparatus: the next stop for new proteins, acting as a sorting and finishing centre before they are shipped to their final destination.
- Organoids: three-dimensional clusters of cells grown in the lab that mimic some features of real organs, such as brain or pancreas tissue.
- Microcephaly: a condition where a baby’s head is significantly smaller than average, usually reflecting reduced brain growth.
TMEM167A appears to sit at the crossroads of ER and Golgi traffic. When it is faulty, the whole delivery route for key proteins falters. In beta cells that means insufficient insulin; in neural stem cells, it may translate into faulty neuron birth and miswired circuits.
Future scenarios and unanswered questions
One practical scenario researchers already consider is personalised therapy based on a child’s specific mutation. If a baby with TMEM167A-related diabetes responds even slightly to agents that relieve cell stress, clinicians might combine classic insulin therapy with protective drugs that keep remaining beta cells alive longer.
Another open question concerns the brain. If the same molecules that help beta cells cope with stress also benefit neural cells, early treatment might, one day, soften the impact on development. Testing such ideas would require careful, long-term studies, strict safety monitoring and input from ethics committees, especially when treating newborns.
For now, the TMEM167A story shows how advanced genetics and cell modelling can connect seemingly separate symptoms — high blood sugar and brain malformations — back to a single molecular fault that shapes life before birth.