The Diseases We Study

Carbamoyl phosphate synthetase 1 (CPS1) deficiency is the most severe urea cycle disorder, caused by variants in the CPS1 gene resulting in life-threatening hyperammonemia and encephalopathy in newborns. Liver transplantation is the only curative treatment for this disease, and it has substantial morbidity while requiring lifelong immunosuppression. While patients wait for a compatible transplant, they are at risk of recurrent episodes of hyperammonemia due to infection or other minor physiologic stressors that could cause further irreversible neurologic damage resulting in long-term cognitive impairments and potentially an early death. We are establishing a workflow for developing corrective editing treatments for N-of-1 patients with rare metabolic diseases such as CPS1 deficiency and other urea cycle disorders within a few months of birth.

1. Learn More about how CPS1 works here: https://www.nejm.org/doi/full/10.1056/NEJMe2505721

Phenylketonuria (PKU) is an autosomal recessive, inborn error of metabolism caused by mutations in the gene encoding the hepatic enzyme phenylalanine hydroxylase (PAH).  Loss of PAH, which catalyzes hydroxylation of the amino acid phenylalanine (Phe) into tyrosine, leads to the neurotoxic accumulation of dietary Phe. Without strict compliance to a Phe-free diet, patients are at risk of developing intellectual disabilities, motor deficits, psychiatric disorders, and seizures. Our lab is working on gene therapies that correct Phe metabolism while improving neurologic function and quality of life in PKU patients.   

1. Gautier, M. K., King, K., Han, Y., Said, H., Alameh, M.-G., Wang, X., Hong, X., Musunuru, K. & Ahrens-Nicklas, R. C. In vivo adenine base editing rescues brain biochemistry and improves motor deficits in a common phenylketonuria variant. Mol. Ther. Adv. 34, 201760 (2026).

Multiple sulfatase deficiency (MSD) (MIM #272200) is an ultra-rare, inherited lysosomal storage disorder (LSD) characterized by the functional deficiency of all cellular sulfatases. Sulfatases are a group of 17 enzymes that break down sulfated substrates such as glycosaminoglycans (GAGs), sulfolipids, and steroid sulfates. In MSD, a severe reduction or complete absence of all sulfatase activities occurs as a result of biallelic pathogenic variants in the gene SUMF1, encoding the sulfatase modifying factor formylglycine-generating enzyme (FGE). As most sulfatases are located in the lysosomes of cells, substrates accumulate here in patients causing lysosomal disease manifestations. Patients often present with psychomotor retardation and neurological deterioration, as well as vision and hearing loss, organomegaly, corneal clouding, cardiac valve disease, dysostosis multiplex, contractures, ichthyosis, and premature death. Currently, there are no disease-modifying therapies for MSD. Our lab is interested in further uncovering the pathological mechanisms underlying MSD by developing novel iPSC-based cell models, as well as developing cell and gene therapies to treat patients. We work closely with MSD patient and family foundations to help support our work.

1. Pham V, Sertori Finoti L, Cassidy MM, Maguire JA, Gagne AL, Waxman EA, French DL, King K, Zhou Z, Gelb MH, Wongkittichotee P, Hong X, Schlotawa L, Davidson BL, Ahrens-Nicklas RC. A novel iPSC model reveals selective vulnerability of neurons in multiple sulfatase deficiency. Mol Genet Metab. 2023 Dec 21:108116. doi: 10.1016/j.ymgme.2023.108116. Epub ahead of print. PMID: 38161139.

2. Adang LA, Mowafy S, Herbst ZM, Zhou Z, Schlotawa L, Radhakrishnan K, Bentley B, Pham V, Yu E, Pillai NR, Orchard PJ, De Castro M, Vanderver A, Pasquali M, Gelb MH, Ahrens-Nicklas RC. Biochemical signatures of disease severity in multiple sulfatase deficiency. J Inherit Metab Dis. 2023 Oct 23. doi:10.1002/jimd.12688. PMID: 37870986.

3. Adang LA, Schlotawa L, Groeschel S, Kehrer C, Harzer K, Staretz-Chacham O, Silva TO, Schwartz IVD, Gärtner J, De Castro M, Costin C, Montgomery EF, Dierks T, Radhakrishnan K, Ahrens-Nicklas RC. Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra-rare disease. J Inherit Metab Dis. 2020 Nov;43(6):1298-1309. doi: 10.1002/jimd.12298. Epub 2020 Aug 20. PMID: 32749716; PMCID: PMC7693296.

4. Schlotawa L, Adang LA, Radhakrishnan K, Ahrens-Nicklas RC. Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification. Int J Mol Sci. 2020 May 13;21(10):3448. doi: 10.3390/ijms21103448. PMID: 32414121; PMCID: PMC7279497.

CLN3 Disease, colloquially known as Batten’s Disease or Juvenile Neuronal Ceroid Lipofuscinoses (JNCL) is a form of lysosomal storage disease that arises from mutations in the CLN3 gene, which encodes CLN3 protein. JNCL is a rare, pediatric genetic neurodegenerative disorder characterized by progressive vision loss onset at ages 4-7, seizures at approximately age 10, parkinsonism, problems walking, difficulty with speech and language, and death between ages 15-30. Loss of CLN3 function leads to lysosomal storage, however, the exact function of the CLN3 protein remains to be elucidated. Our group has recently discovered that early synaptic dysfunction precedes storage accumulation or neuronal death in CLN3 models. We are now working to understand the mechanisms of synaptic dysfunction in CLN3 disease and are developing gene therapies that can improve neurologic function in patients.

1. Ahrens-Nicklas RC, Tecedor L, Hall AF, Kane O, Chung RJ, Lysenko E, Marsh ED, Stein CS, Davidson BL. Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage accumulation. Mol Ther. 2022 Jul 6;30(7):2464-2473. doi: 10.1016/j.ymthe.2022.03.025. PMID: 35395398; PMCID: PMC9263320.

2. Ahrens-Nicklas RC, Tecedor L, Hall AF, Lysenko E, Cohen AS, Davidson BL, Marsh ED. Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder. JCI Insight. 2019 Nov 1;4(21):e131961. doi: 10.1172/jci.insight.131961. PMID: 31573978; PMCID: PMC6948765.

3. Singh, J.B., Burris, D.M., Bhuyan, S. et al. CLN3 disease disrupts very early postnatal hippocampal maturation. Sci Rep 15, 24411 (2025). https://doi.org/10.1038/s41598-025-02010-1

Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) is one of the most common inherited metabolic disorders, characterized by a loss-of-function mutation in the enzyme Medium-Chain Acyl-CoA Dehydrogenase (MCAD). This enzyme is primarily responsible for beta-oxidation, or the catabolism of fatty acids to fuel respiration. Without MCAD, the cell can only use limited and quickly expendable sugars instead of its energy-rich fat stores, which is especially stressful for tissues with heavy bioenergetic demands such as the heart, brown adipose tissue, skeletal muscle, and liver. Thus, during catabolic stress, such as during illness or prolonged fasting, MCADD patients can suffer from severe pathologies, including hypoglycemia, seizures, coma, brain damage, and death. As a lab, we are interested in further understanding MCADD pathology and applying gene editing technologies to correct disease-causing mutations in vivo, with the goal of improving future MCADD therapeutics.

1. Ahrens-Nicklas RC, Pyle LC, Ficicioglu C. Morbidity and mortality among exclusively breastfed neonates with medium-chain acyl-CoA dehydrogenase deficiency. Genet Med. 2016 Dec;18(12):1315-1319. doi: 10.1038/gim.2016.49. PMID: 27148938; PMCID: PMC5538896.

Disorders of branched chain amino acid (BCAA) metabolism are rare inborn errors of metabolism that can lead to devastating neurologic dysfunction. Using novel iPSC and mouse models, we are investigating the pathophysiology of several BCAA disorders. Our goal is to understand the role of BCAA metabolism in the brain. Building on our mechanistic studies, we are developing a variety of targeted therapeutic approaches. Disorders we are studying include:

• Maple Syrup Urine Disease

• BCKDK Deficiency

• BCAT1 Deficiency

1. Ohl L, Kuhs A, Pluck R, Durham E, Noji M, Philip ND, Arany Z, Ahrens-Nicklas RC. Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency. bioRxiv [Preprint]. 2023 Oct 12:2023.10.12.560929. doi: 10.1101/2023.10.12.560929. PMID: 37873402; PMCID: PMC10592755.

2. Xu J, Jakher Y, Ahrens-Nicklas RC. Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders. Int J Mol Sci. 2020 Oct 11;21(20):7490. doi: 10.3390/ijms21207490. PMID: 33050626; PMCID: PMC7590055.