From a parent’s perspective, she was first and foremost a doctor, and in every sense of the word she tried to help the children afflicted with Peroxisomal Biogenesis Disorders (Zellweger’s Syndrome). She carried a small black doctor bag with her. In it were a few simple tools, a tape measure, a hammer, a stethoscope, and an examination light. She had no nurses or attendants. She did not employ impressive, expensive machines to aid her investigation of her patients. Quietly she observed, played with, and asked the parent’s questions as a means of evaluating the child. Her demeanor usually was calm and reflective, offering positive hope with her gentle smile.
Her empathy and compassionate heart lead her to be a researcher, a profession which always required funding. At one point she even sold her house in order to keep the children supplied with the DHA-EE supplement and did her laboratory work in her own wash room. As a professional Dra. Martinez embraced the highest of ethics to provide for a needy child. She could not deny any child with a deficiency the supplement he needed to live the fullest possible life, even if it would have furthered her research. As a clinician, she could tell from a child’s blood work if he was deficient in something or if he was ingesting too much of a wrong thing. Because of her close observation of each patient, Dra. Martinez as an outstanding researcher understood the Zellweger’s Disorder better than anyone else in her time.
Dra. Martinez‘ last published research awaits someone to carry forward her last discovery.
History of Manuela Martinez’s Work
Manuela Martinez is a pediatrician and a researcher, dedicated for many years to the study of the developing human brain and the influence of nutrition on brain maturation. It was the continuity of her work along these years that led Dra. Martinez to discover a new lipid abnormality in a group of congenital metabolic diseases: the peroxisomal disorders. This finding led Dra. Martinez to device a new treatment for those severe patients and since then, she is devoted to the study of patients with peroxisomal disorders and their treatment.
Early studies on nutrition and normal brain development
Everything started in 1972, with the study of lipid accretion in the premature and newborn infants. There is a developmental period when the brain becomes vulnerable to nutritional deficiencies and M. Martinez wanted to assess the limits of that period in the human species, something that was not known at the moment. Her first studies on the lipid profiles in the forebrain and cerebellum were published in 1974 and they showed that lipids and the most polyunsaturated fatty acids (PUFA) started to accumulate very fast in the forebrain at 32 weeks of gestational age. When comparing the lipid profiles in the human forebrain and cerebellum, M. Martinez found that, in contrast to the rat, in the human species, lipids accumulate much more rapidly in the forebrain than in the cerebellum. As a result (and also in contrast to the rat) in the human, the forebrain is more vulnerable to nutritional aggressions than thecerebellum. In fact, when malnutrition started very early in life, M. Martinez proved that only the forebrain showed a decrease in myelin lipids.
In a more detailed study on myelination in the human developing brain, M. Martinez found that myelin in the neonate and young infant is strikingly similar to that in the adult brain, structurally as well as biochemically. Also in contrast with studies on rat myelination, in the human species, nutritional deficiencies affect the amount rather than the quality of myelin.
Another study on the influence of nutrition on the fatty acid patterns of liver and brain showed that an excess of linoleic acid (18:2w6) may be damaging to the premature infant. When given in milk formulas or in formulas for total parenteral nutrition, such an excess of 18:2w6 produces a decrease in the levels of docosahexaenoic acid (DHA, 22:6w3), the most important PUFA in neural tissues. Even the infant retina may be deprived of DHA when the formulas used have too high w6/w3 PUFA ratios.
Research on peroxisomal disorders
Dra. Martinez’s research took a new course in 1987, when she found that the brain, liver, and kidneys of a patient with the Zellweger syndrome (a lethal congenital disorder characterized by the lack of functional peroxisomes) had extremely low levels of DHA. She could later prove that this is a constant finding in patients with defective peroxisomal biogenesis. Due to the great importance attributed to DHA in cell membranes, especially in the brain and photoreceptor cells of the retina, M. Martinez hypothisized that the DHA deficiency found in peroxisomal disorders could cause much of the damage in these patients or, at least, could contribute to the severity of some of their signs, like bindness and neurological disease. A logical consequence of this hypothesis was to consider the possibility of giving peroxisomal-disorder patients the DHA they lacked, in an attempt to improve their symptoms. Thus, the current research line of M. Martinez started.
Restoring the DHA levels in the brains of peroxisomal-disorder patients
To date, 30 peroxisomal patients have been treated and the results are very promising (see A ray of hope: DHA therapy and nutrition), indicating that DHA can restore the levels of DHA in the brain and retina. Indeed, treatment with DHA ethyl ester has produced biochemical improvement (normalization of DHA, increase in plasmalogens, and decreases in the levels of the very long chain fatty acids 26:0 and 26:1). These analytical improvements parallel or followed normalization of the DHA levels. Clinically, DHA therapy produced liver, visual, and neurological amelioration. Most interestingly, myelination markedly improved in many cases, as checked by brain MRI. This suggests an important role for DHA in the formation of myelin during early brain development.
In accordance with her previous findings, M. Martinez recommends that DHA be given as soon as possible during brain development. Indeed, to be effective DHA should ideally be provided during the third trimester of gestation or, at least, as soon as possible after birth. Unfortunately, this is rarely possible, since diagnosis is usually made far too late. In general, there is much lack of information about peroxisomal disorders and other metabolic diseases, regarding diagnosis as well as therapeutical possibilities. The consequence is very bad for the affected children, since treatment initiated too late cannot be fully effective. That is the reason for creating the new Manuela Martinez Foundation for Children with Metabolic Diseases, an institution devised to provide information and early diagnosis, treatment and support to children with peroxisomal disorders and other lipid metabolic diseases.
