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Metabolic Causes of Sudden and Unexpected Death in Early Life

Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life
The Journal of Pediatrics; January 2001; Volume 132, Number 6 (June 1998)
The results of this study support the view that approximately 5% of all cases of sudden infant death are likely caused by an Fatty-acid Oxidation disorder.

Article
By:  Piero Rinaldo, MD

In recent years, genetic disorders have gained unprecedented recognition in clinical medicine. Six to eight percent of children hospitalized in tertiary care hospitals are affected with single-gene defects, and metabolic disorders as a part of this group may soon be acknowledged (finally!) as a major health problem among pediatric patients. To date, however, the collective incidence of metabolic disorders continues to be underestimated and often first attributed to a variety of other causes, ranging from infections to poisoning and even to child abuse.

Among the large number of single-gene disorders that are currently recognized, inborn errors of amino acid, carbohydrate, and fatty acid metabolism deserve special attention. More than one hundred new disorders have been identified over the past 25 years, and our knowledge of their clinical and biochemical manifestations has grown accordingly. We know that the vast majority of these disorders present with life-threatening episodes of metabolic decompensation (acidosis with or without ketosis, hypoglycemia, hyperammonemia, etc.), often within the first year of life. In view of the high mortality rate that is associated to the first occurrence of acute illness, it's not surprising that sudden infant death syndrome (SIDS) has been sporadically associated with a few inborn errors of amino acid and energy metabolism (Table 1). These isolated cases could be interpreted as the result of a delayed diagnosis combined with atypical and/or mild clinical phenotypes, and are unlikely to represent a significant cause of sudden infant death.

On the other hand, the number of cases which were found to be affected with a fatty acid oxidation (FAO) disorder either postmortem or after the diagnosis of an affected sibling has soared in the last few years. Based on these observations, it has been postulated that FAO disorders might be responsible for 3 to 5% of SIDS cases, and possibly a much greater proportion of children who die suddenly and unexpectedly from birth to five years of age. If this estimate does not impress you, consider that it translates into 200-400 cases per year in the US alone!

Fatty acid oxidation plays a major role in energy production during periods of fasting. When the body's supply of glucose is depleted, fatty acids are mobilized from adipose tissue, taken up by the liver and muscles, and step-wise oxidized (broken down) to their final product, acetyl-CoA. More than 25 enzymes are involved in this complex pathway, and each of them is required to guarantee a continuous supply of energy to the body. At the cellular level, long-chain fatty acids are predominantly metabolized in mitochondria. Following the carnitine-dependent transport of fatty acids into the mitochondria, oxidation consists of cycles of four sequential reactions catalyzed first by membrane-bound enzymes (long-chain species), and then by a different set of soluble enzymes (medium- and short-chain), producing at the end of each cycle a molecule of acetyl-CoA and a fatty acid with two fewer carbons. The latter re-enters the cycle until it is completely consumed. In the liver, acetyl-CoA is the building block for the synthesis of ketone bodies (acetoacetic acid and 3-hydroxy butyric acid), which enter the blood stream and provide an alternative substrate for production of energy in other tissues when the supply of glucose is insufficient to maintain a normal level of energy.

Inherited FAO disorders represent a new and rapidly expanding class of metabolic diseases. Eighteen FAO disorders are known to date, and at least 13 are known to be responsible for cases of sudden and unexpected death from birth to early childhood (Table 2). If death occurs in the first year of life, some of these cases are diagnosed as SIDS, especially when growth and development were normal preceding the time of death. FAO disorders may actually present with a variety of clinical manifestations, including metabolic decomposition during fasting, (low levels of ketone bodies in blood and urine) hypoglycemia and abnormal function of fatty acid-dependent tissues like the liver, skeletal muscles, and the heart. In the neonatal period, a significant proportion of affected cases present with hypoglycemia within the first 48 hours after birth. Depending on several factors (type of feeding, schedule, etc.), the severity of these episodes may vary from relatively mild hypoglycemia, which responds rapidly to therapy, to neonatal sudden death (Table 2). Continued on Page 6

Table 2. Fatty acid b-oxidation disorders

Hypoglycemia and the accumulation of toxic by-products of fatty acids, which can't be broken down, are considered the underlying mechanisms of these manifestations.

Technically speaking, FAO disorders do belong to the family of the organic acidemias/-urias because the trademark biochemical finding in the majority of these disorders is the urinary excretion of C6-C8 dicarboxylic acids (by-products of fatty acids), a pattern known as dicarboxylic aciduria. Glutaric acid, for example, is also a dicarboxylic acid, but its chain length is C5 (in other words, there are five carbon atoms in the molecule).

The postmortem diagnosis of Fatty-acid Oxidation Disorders
I anticipate it will sound painfully familiar to many readers, but I would like to take this opportunity to stress the absolute importance of performing an autopsy in all cases of children who die suddenly and unexpectedly. Unfortunately, the decision of granting permission to perform an autopsy has to be made quickly, in a moment of terrible anguish, and even if your instinct is totally against it. However, without the findings of a postmortem examination and the opportunity to collect body fluid and tissue specimens for specific metabolic investigations, chances are strongly against the possibility that you will never know the cause of what happened. To elaborate on the general issue of what needs to be done to diagnose these conditions before an autopsy is performed, I have a few suggestions that may offer some guidance under these tragic circumstances:

1. Most importantly, ask your doctor to contact the Medical Examiner and make sure that the following specimens are collected and processed/stored properly:
   1. Skin biopsy. A line of cultured fibroblasts could be successfully grown from a skin biopsy performed up to 48 hours after the time of death. A good alternative source of fibroblasts is a biopsy of the Achilles tendon;
   2. All available body fluids (any volume). In particular, urine (traces of urine embedded in the bladder posterior wall could be effectively recovered with a cotton swab), plasma/serum (making spots on filter paper is a good way to
   3. save it), and bile (see below). If promptly frozen at -20°C, these specimens will last almost indefinitely. Dried spots on filter paper can be stored at room temperature;
   4. A small (2-5 g) fragment of liver, placed in a plastic container and immediately frozen (-20°C). For biochemical testing, collection of tissues may be delayed to a maximum of 72 hours after the time of death.
2. Ask that special attention is given to the microscopic examination of the liver, possibly to include a special stain for fat called Oil red O.

3. Finally, ask your doctor to obtain for you a complete copy of the autopsy report when ready (beware that it may take several weeks to be signed out and released), not a brief summary and/or a copy of the official death certificate.
   
4. A possible diagnosis of a FAO disorder may be suspected from the presence of moderate to severe fatty infiltration of the liver and other tissues, a postmortem finding which is frequently overlooked as non-specific. Even if a suspicion was properly raised, a common experience is that the consequent work-up is hampered by inadequate collection and/or storage of specimens. In the belief that the presence of liver fatty changes in an infant/child who dies suddenly and unexpectedly, should prompt the evaluation of a possible metabolic etiology, a few years ago we decided to seek alternative diagnostic methods based on the principle that testing should be directed to more accessible postmortem samples. As a first step in this direction, we developed a new biochemical method for the analysis of diagnostic metabolites in postmortem liver. Using this method, findings which are consistent with a FAO disorder include markedly reduced glucose concentration and elevated concentration of selected fatty acids (see references listed below). In addition, we later realized that the determination of total carnitine concentration in the supernatant of the liver homogenate represents an additional and valuable diagnostic parameter.

It is well known that formation of carnitine esters is involved in four critical functions: a) import of long-chain fatty acids into the mitochondria; b) export of physiological short-chain acyl-CoA groups from the mitochondria; c) buffering of the mitochondrial free CoA/esterified CoA ratio; and, d) enhancing of urinary excretion of potentially toxic acyl-CoA groups when they accumulate as a consequence of a metabolic block.

In the case of long-chain FAO disorders, however, urinary excretion of long-chain acylcarnitines species does not take place because they are poorly soluble in water. Recently, we have shown that acylcarnitine species were present in very high concentrations in bile collected postmortem from nine metabolic patients. Based on this information, we believe that not only the analysis of the biliary excretion of acylcarnitines could lead to a new understanding of the role of carnitine-mediated detoxification in metabolic disorders, but could also provide a valuable diagnostic tool, especially in cases where no other body fluids are available for biochemical testing.

In summary, the diagnostic protocol currently in use in our laboratory for the postmortem diagnosis of FAO disorders includes the following parameters:

1. Liver histology (fatty infiltration)
               C₈-C₁₈ fatty acids and glucose concentrations in liver homogenate
2. Total and free carnitine in liver homogenate and bile
3. Acylcarnitine profile in bile
4. Acylglycines and organic acids in urine (if available)

The postmortem diagnosis of FAO disorders in sudden death victims is important for genetic accurate counseling and for the evaluation of siblings who may be at risk for significant, yet often preventable, morbidity and mortality. For these reasons, it is critical to raise the awareness of FAO disorders and other metabolic disorders as potential causes of sudden and unexpected death in early life. This effort should focus not only on infants who meet the traditional SIDS criteria, but especially on cases whose cause of death is attributed to an infection like pneumonia or sepsis.

References
Boles RG, Martin SK, Blitzer MG, Rinaldo P. Biochemical diagnosis of fatty acid oxidation disorders by metabolite analysis of post-mortem liver. Hum Pathol 25:735-741, 1994.

Rashed MS, Ozand PT, Bennett MJ, Barnard JJ, Govindaraju DR, Rinaldo P. Diagnosis of inborn errors of metabolism in sudden death cases by acylcarnitine analysis of postmortem bile. Clin Chem 41:1109-1114, 1995.

Boles RG, Boesel C, Rinaldo P. Sudden death beyond SIDS. Pediatr Pathol & Lab Med 16:691-693, 1996.

Rinaldo P, Stanley CA, Sanchez LA, Stern HJ. Sudden neonatal death in carnitine transporter deficiency. J Pediatr, in press.

Boles RG, Buck EA, Blitzer MG, Platt MS, Martin SK, Yoon HR, Madsen JA, Reyes-Mugica M, Rinaldo P. Retrospective biochemical screening of fatty acid oxidation disorders in postmortem liver of 418 cases of sudden unexpected death in the first year of life. Submitted.

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