SLC4A4 encodes electrogenic sodium bicarbonate cotransporter NBCe1, prominently expressed in kidney and brain. Recessive loss-of-function variants in SLC4A4 cause proximal renal tubular acidosis, no brain edema. In the brain, NBCe1 is expressed by astrocytes, where it regulates pH and mediates astrocyte volume changes. Here we describe a novel dominant variant in SLC4A4 in patients with brain edema and investigate how it affects NBCe1 function. Genetic studies identified a novel gene variant in three unrelated pediatric patients with the same MRI pattern of cerebral subcortical white matter signal abnormality and swelling, and medulla lesions. Immunohistochemical and electrophysiological experiments were performed to determine the localization of the transporter in the brain and the functional consequence of the patient variant. The same heterozygous variant in SLC4A4 was found in all three patients and one parent. The children displayed infantile-onset progressive macrocephaly, motor and cognitive impairment, autism, epilepsy, and recurrent episodes of increased intracranial pressure. Bicarbonate treatment of two patients led to clinical and MRI improvement. Immunohistochemistry revealed that brain NBCe1 is mainly present in astrocytes, more in cortex than white matter. Functional experiments revealed impaired transporter activity of mutant NBCe1 due to reduced membrane expression and a prominent depolarizing ion leak. The most likely pathomechanism of this novel SLC4A4-related disease is that a depolarizing leak in NBCe1 disrupts astrocyte pH regulation, promoting swelling and impairing volume control. These findings uncover a previously unrecognized mechanism of genetic brain edema and establish NBCe1 as a critical modulator of astrocyte homeostasis.

Proximal renal tubular acidosis (RTA) results from impaired bicarbonate reabsorption in the proximal renal tubule, leading to a normal anion gap metabolic acidosis and electrolyte abnormalities. We report the case of a 16-year-old previously healthy female who presented with recurrent episodes of hypotension, dizziness, and generalized weakness over one month. Laboratory evaluation demonstrated severe hypokalemia, hyperchloremic metabolic acidosis with a normal anion gap, and glucosuria in the absence of hyperglycemia, with preserved renal function. Extensive evaluation for endocrine and autoimmune causes was unrevealing. A detailed review of medications and supplements identified recent initiation of high-dose biotin supplementation (2,500 µg daily) for cosmetic purposes. A strong temporal association was noted between biotin exposure and symptom onset, with rapid clinical and biochemical improvement following discontinuation. Two months later, inadvertent re-exposure to biotin resulted in recurrence of symptoms and laboratory abnormalities, which again resolved promptly after cessation of the supplement. The patient was managed with intravenous fluids, potassium supplementation, and avoidance of biotin, leading to sustained resolution of symptoms. At one-month follow-up, she remained asymptomatic with normal electrolyte levels and preserved renal function. This case identifies biotin as a rare, reversible cause of proximal RTA and underscores the importance of obtaining a thorough supplement history when evaluating patients with otherwise unexplained metabolic acidosis.

Renal tubular acidosis (RTA) often presents as failure to thrive in children. In a resource-limited country, the diagnosis of renal tubular acidosis can be delayed or even missed because of the co-existing high burden of malnutrition. Here we report a case of a neonate/infant who presented with diarrhoea and failure to thrive and subsequently developed septic shock. During the management of the child, proximal renal tubular acidosis was diagnosed based on the persistence of metabolic acidosis with hyperchloremia. Proximal renal tubular acidosis (pRTA) can lead to complications, such as electrolyte disorders, bony deformities. Prompt diagnosis, appropriate treatment, and long-term follow-up are imperative for achieving good outcomes.

Cadmium exposure from jewellery-making fumes can damage bones and kidneys. In five goldsmiths, we found osteoporosis, fractures, and renal dysfunction linked to high cadmium levels. Both direct toxicity and indirect effects through kidney damage and hormones contributed. Awareness and early detection may prevent irreversible complications. Cadmium (Cd) is a highly toxic heavy metal with established skeletal and renal toxicity. Inhalation of Cd fumes during jewellery-making is an underrecognized occupational hazard in India. We report five goldsmiths with chronic Cd exposure who developed varying patterns of metabolic bone disease, aiming to highlight the diverse mechanisms of Cd-induced osteopathy. Five patients with occupational exposure to Cd in jewellery-making were evaluated through detailed clinical history, biochemical investigations (renal and metabolic profile, bone turnover markers, intact fibroblast growth factor 23 levels), dual-energy X-ray absorptiometry (DXA), and Cd measurement by inductively coupled plasma mass spectrometry. Renal tubular function was assessed with urinary β2-microglobulin and serum uric acid. All five patients exhibited skeletal involvement, ranging from osteopenia to severe osteoporosis and fractures. Case 1 had proximal renal tubular acidosis, hypophosphatemic osteomalacia, secondary hyperparathyroidism, and progressive cortical bone loss, with clinical improvement after supplementation therapy. Case 2 showed proximal myopathy, osteoporosis, and cardiomyopathy, with renal phosphaturia. Cases 3-5 demonstrated primarily cancellous bone loss with variable renal tubular dysfunction and markedly elevated Cd levels. Hypophosphatemia was mediated by both tubular damage and FGF23-dependent mechanisms. Hypouricemia emerged as a sensitive biomarker of early tubular injury. Chronic occupational Cd exposure in goldsmiths causes diverse skeletal manifestations through direct osteotoxicity, hypophosphatemia from renal tubular dysfunction and FGF23 excess, and secondary hyperparathyroidism. The toxic effect preferentially involves cancellous bone, while renal-mediated mechanisms contribute to cortical bone loss. Early recognition via occupational history, supported by simple biomarkers such as serum uric acid, is essential to prevent irreversible complications. Supplementation with calcium, phosphate, vitamin D analogues, and supportive therapy can stabilize bone health and improve outcomes.

The BCS1L gene encodes a mitochondrial chaperone which inserts the Fe2S2 iron-sulfur Rieske protein into the nascent electron transfer complex III. Variants in the BCS1L gene are associated with a spectrum of mitochondrial disorders, ranging from mild to severe phenotypes. Björnstad syndrome, a milder condition, is characterized by sensorineural hearing loss (SNHL) and pili torti. More severe disorders include Complex III Deficiency, which leads to neuromuscular and metabolic dysfunctions with multi-systemic issues and Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, and Lactic Acidosis syndrome (GRACILE). The severity of these conditions varies depending on the specific BCS1L mutation and its impact on mitochondrial function. This study describes a 27-month-old child with SNHL, proximal renal tubular acidosis, woolly hypopigmented hair, developmental delay, and metabolic alterations. Genetic analysis revealed a homozygous BCS1L variant (c.38A>G, p.Asn13Ser), previously reported in a patient with a more severe phenotype that, however, was not functionally characterized. In this work, functional studies in a yeast model and patient-derived fibroblasts demonstrated that the variant impairs mitochondrial respiration, complex III activity (CIII), and also alters mitochondrial morphology in affected fibroblasts. Interestingly, we unveil a new possible mechanism of pathogenicity for BCS1L mutant protein. Since the interaction between BCS1L and CIII is increased, this suggests the formation of a BCS1L-containing nonfunctional preCIII unable to load RISP protein and complete CIII assembly. These findings support the pathogenicity of the BCS1L c.38A>G variant, suggesting altered interaction between the mutant BCS1L and CIII.