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Inherited Metabolic Disease Group

Group members (Permanent staff)
Surita Meldau Senior Medical Scientist / Lecturer
Kashief Khan Medical Technologist
Professor George van der Watt Pathologist
Group members (Students)
Ronald Dalmacio MMed student
Sarah Lampert MSc Student

OVERVIEW

Metabolic disease is a large group of disorders that are individually rare, but have in common a defect in energy metabolism in the cell…
The NHLS IMD molecular laboratory at GSH is currently the only reference laboratory in Southern Africa focussing on molecular diagnosis of IMDs. Referrals are received from both private and state sectors as well as occasionally from across our borders.  Obtaining a molecular diagnosis is important for affected families. It allows screening of future affected pregnancies, as well as carrier testing of family members to determine risk of transmitting. the disease to their offspring.
The metabolic disorders that affect South African patients differ from that seen in other populations. We have several founder variants that account for most cases and point mutation screens are routinely done for these disorders at the IMD molecular diagnostic lab.  These include galactosemia, MPV17 neurohepatopathy, glutaric aciduria type 1, primary hyperoxaluria and cystinosis.  However, there are many other disorders affecting individual families in South Africa.
 

CURRENT RESEARCH PROJECTS

Mitochondrial Disease in South Africa (Ongoing Research)

Mitochondrial disease is a large group of conditions that are individually rare but have in common a genetically inherited defect in the mitochondrial respiratory chain.  The result is invariably an energy production crisis and can potentially cause just about any symptom in any tissue at any age and is thought to have a minimum prevalence of about 1 in 5000 live births worldwide.  
Diagnosing mitochondrial disease can be extremely complex as clinical presentation can vary even between individuals in the same family.  Biochemical markers, histology, and enzymology (not currently available in South Africa) can merely give clues but in most cases making a diagnosis relies almost entirely on confirmation through identification of an underlying genetic defect.  
However, mutations in any one of more than 400 nuclear DNA (nDNA) and all 37 mitochondrial DNA (mtDNA) genes (found inside the mitochondria of most cells in the human body) can be at fault.
We have recently published an audit of all the genetic findings in the South African diagnostic sector, describing the underlying causes of this group of disorders in Southern Africa and highlighting the gaps in our knowledge of this disease on the African continent.
 
Understanding the genetic basis of mitochondrial disease in South African patients is essential in ensuring the most optimal testing strategies are in place for future patients. 

Substudies:
• Investigation of the genetic defects underlying Leigh syndrome and mtDNA maintenance disorders in South African paediatric patients.
• Investigating haplogroup contexts of pathogenic mtDNA mutations in South African patients.
• MPV17 disease in South Africa (See below)

 

MPV17 mitochondrial neurohepatopathy in South African patients (Ongoing work)

MPV17 deficiency is characterised by infantile onset liver disease and neurological features such as hypotonia, developmental delay, failure to thrive and neuropathy.  It is primarily a lethal disorder of infancy and is a very rare disorder worldwide.
We have recently identified a single MPV17 nonsense mutation in 24 Black South African infants presenting with mitochondrial neurohepatopathy, and subsequently demonstrated a high carrier frequency (1 in 68; 95% CI: 1/122 – 1/38) and predicted population disease incidence (1 in 18 496; 95% CI; 1/59536 – 1/5776).  This incidence is much higher than any other population described.

The exact function of the human MPV17 protein is still uncertain, although it appears to play a role in regulation of oxidative stress and dNTP maintenance in the mitochondria.

It is further unclear why some patients survive for months or years, while others decompensate and demise only days after birth. It is not inconceivable that environmental factors or exposure to pathogens or certain pharmaceutical compounds that are known to cause excessive ROS production and/or mtDNA depletion, may put the affected mitochondria under increased pressure – leading to earlier disease progression. Identification and understanding of such modifying factors may lead to a better understanding of the precise disease mechanism and point to likely treatments outcomes and better management strategies.

 

Population carrier frequency determination of pathogenic variants in four inborn errors of metabolism in a Western Cape South African population.

The improved clinical awareness and genetic sequencing capabilities for confirming disease causing variants of inborn errors of metabolism (IEM) brought about the determination of local pathogenic variants. This study aims to determine the carrier frequency of four recurring IEM-causing pathogenic variants recently identified in our black African population, namely, hyperphosphataemic familial tumoral calcinosis (hFTC), succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency, glycogen storage disease (GSD) type 1a, and multiple mitochondrial dysfunction syndrome type 2 (MMDS-2). Determination of prevalence within a population is one of the fundamental measures within epidemiological studies, and defines the burden of disease within a population, in each location, at a particular time. In a resource-constrained setting, the importance of prevalence studies allows researchers to decide the impact of a condition, by using statistical evidence to guide dissemination of resources, and provides context in disease diagnosis. 

The proposed objectives utilized to determine the presence of these variants within our cohort will be development of separate allele specific ARMS-PCR, combination into a multiplex assay and DNA analysis. This methodology has also been useful in determining the frequency of numerous genetic variants. The possible coupling of ARMS-PCR with multiplex genetic testing, will further increase throughput by combining all these individual assays into a single run, thereby saving time and money. 

The contribution of the research will assist in determination of disease prevalence of the four abovementioned disorders, within the Western Cape, black South African population. The methodology used in this study additionally has potential for use in screening of these variants, thereby improving time to diagnosis.

 

RECENT RELEVANT PUBLICATIONS

•  Swart C, Meldau S, Centner CM, Marais AD, Omar F. 

Validation of PHASE for deriving N-acetyltransferase 2 haplotypes in the Western Cape mixed ancestry population. 

Afr J Lab Med. 2020;9(1), a988. https://doi.org/10.4102/ajlm.v9i1.988

• Meldau S, Owen EP, Khan K, Riordan GT. 

Mitochondrial molecular genetic results in a South African cohort: divergent mitochondrial and nuclear DNA findings. 

J Clin Pathol. 2020 [https://doi.org/10.1136/jclinpath-2020-207026] 

• Meldau S, Fratter C, Bhengu LN, et al. 

Pitfalls of relying on genetic testing only to diagnose inherited metabolic disorders in non-western populations - 5 cases of pyruvate dehydrogenase deficiency from South Africa.

Mol Genet Metab Rep 2020;24:100629 doi: 10.1016/j.ymgmr.2020.100629.

• Roberts L, Julius S, Dawlat S, Yildiz S, Rebello G, Meldau S, Pillay K, Esterhuizen A, Vorster A, Benefeld G, Da Rocha J, Beighton P, Sellars SL, Thandrayen K, Pettifor JM, Ramesar RS.

Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B.

Hum Mutat 2020 doi: 10.1002/humu.24094

• Meldau, S., De Lacy R, Riordan G, Goddard L, Pillay K, Fieggen K, Marais D, Van der Watt G. Identification of a single MPV17 nonsense-associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy.

Clin Genet, 2018 [PMID:29318572    DOI:10.1111/cge.13208]

• O’Keefe, H., Queen, R.A., Meldau, S., Lord, P., Elson, J.L. (2018)

Haplogroup context is less important in the penetrance of Mitochondrial DNA complex I mutations compared to mt-tRNA mutations.

J Mol Evol 86:395-403.

• Ng, Y. S., Lax, N. Z., Maddison, P., Alston, C. L., Blakely, E. L., Hepplewhite, P. D., Riordan, G., Meldau, S., Chinnery, P. F., Pierre, G., Chronopoulou, E., Du, A., Hughes, I., Morris, A. A., Kamakari, S., Chrousos, G., Rodenburg, R. J., Saris, C. G. J., Feeney, C., Hardy, S. A., Sakakibara, T., Sudo, A., Okazaki, Y., Murayama, K., Mundy, H., Hanna, M. G., Ohtake, A., Schaefer, A. M., Champion, M. P., Turnbull, D. M., Taylor, R. W., Pitceathly, R. D. S., McFarland, R. and Gorman, G. S.

MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load. EBioMedicine 2018.

• Freercks, R., Meldau, S., Jones, E., Ensor, J., Weimers-Willard, C., Rayner, B. 

Liddle’s syndrome in an African male due to a novel frameshift mutation in the beta-subunit of the epithelial sodium channel gene.

CVJ 28(5):70-72. 2017.

• Meldau, S., G. Riordan, F. Van der Westhuizen, J. L. Elson, I. Smuts, M. S. Pepper and H. Soodyall (2016).

Could we offer mitochondrial donation or similar assisted reproductive technology to South African patients with mitochondrial DNA disease?

S Afr Med J 106(3): 234-236. (Invited editorial)

• Van der Westhuizen, F. H., P. Z. Sinxadi, C. Dandara, I. Smuts, G. Riordan, S. Meldau, A. N. Malik, M. G. Sweeney, Y. Tsai, G. W. Towers, R. Louw, G. S. Gorman, B. A. Payne, H. Soodyall, M. S. Pepper and J. L. Elson (2015). 

Understanding the Implications of Mitochondrial DNA Variation in the Health of Black Southern African Populations: The 2014 Workshop.

Hum Mutat 36(5): 569-571.

• Owen EP, Nandhlal J, Leisegang F, Van der Watt G, Nourse P, Gajjar P.

Common mutation causes cystinosis in the majority of black South African patients. 

Pediatr Nephrol. 2015 Apr;30(4):595-601. doi: 10.1007/s00467-014-2980-7. Epub 2014 Oct 18. PMID: 25326109.

• Haarburger, D., R. Renison, S. Meldau, R. Eastman and G. van der Watt (2013).

Teenaged siblings with progressive neurocognitive disease.

Clin Chem 59(8): 1160-1164.

• Van der Watt, G., E. P. Owen, P. Berman, S. Meldau, N. Watermeyer, S. E. Olpin, N. J. Manning, I. Baumgarten, F. Leisegang and H. Henderson (2010). 

• Glutaric aciduria type 1 in South Africa-high incidence of glutaryl-CoA dehydrogenase deficiency in black South Africans.

Mol Genet Metab 101(2-3): 178-182.

• Fukao T, Kursula P, Owen EP, Kondo N.

Identification and characterization of a temperature-sensitive R268H mutation in the human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene. 

Mol Genet Metab. 2007 Nov;92(3):216-221.