Saturday, March 29, 2008

A Little Easier To Comprehend

Hailey's Wish
A Ray of Hope

1. What are mitochondria?

Mitochondria (plural for mitochondrion) are sometimes described as cellular “power plants” because among other things, mitochondria are responsible for creating more than 90% of the energy needed by the body to sustain life and support growth. In addition to making energy, mitochondria are also deeply involved in a variety of other activities, such as making steroid hormones and manufacturing the building blocks of DNA.

2. What is a mitochondrial disease?
Mitochondrial diseases result when your body’s mitochondria fail to function properly. Your body’s organ systems are severely affected when your mitochondria can’t provide the energy needed to keep them running. Some parts of the body that require the most energy to function are: the brain, heart, liver, skeletal muscles, kidneys, endocrine and respiratory systems.

3. What are some symptoms of a mitochondrial disease?
Given the fact that mitochondria are responsible for fueling nearly all of the body’s energy needs, there is a long list of symptoms depending on which organ or tissue is having the “energy crisis.” When symptoms arise from three or more organ systems a mitochondrial disease should definitely be considered.

poor growth (failure to thrive)
muscle weakness, poor coordination
sensory (vision, hearing) problems
reduced mental functions
disease of the organ (heart, liver)
respiratory problems
lactic acidosis
gastro-intestinal disorders and swallowing difficulties
developmental delays
movement disorders (dystonia, muscle spasms, tremors, chorea)
brain atrophy
4. How common are mitochondrial diseases?
It is now said that mitochondrial diseases are nearly as common as childhood cancer! One in 4,000 children born in the United States every year will develop a mitochondrial disorder by age 10. In adults, many diseases of aging have been found to have defects of mitochondrial function. These include, but are not limited to, type 2 diabetes, Parkinson’s disease, atherosclerotic heart disease, stroke, Alzheimer’s disease, and cancer. In addition, many medicines can injure the mitochondria.

5. When do doctors suspect that a person may have a mitochondrial disorder?

Different symptoms indicative of mitochondrial diseases may present over time. As patients begin to present with multiple catastrophic symptoms it can be hard for physicians to pinpoint the main cause. It is crucial that they never remove or set aside a symptom to try and diagnose the problem. All symptoms must be given consideration.

Mitochondrial disease should be suspected when:

A “common disease” has atypical features that set it apart from the pack
Three or more organ systems are involved
Recurrent setbacks or flare ups in a chronic disease occur with infections

6. Is there a cure for mitochondrial diseases?
There is not a cure for mitochondrial diseases. Doctors must look at each patient on a case-by-case basis and try to develop a treatment plan. Treatment may involve special diets and/or a combination of vitamins, and reducing any stress on the body.

7. How is a mitochondrial disease inherited?
The types of mitochondrial disease inheritance include:

Nuclear DNA (DNA contained in the nucleus of the cell) inheritance. Also called autosomal inheritance.

— If this gene trait is recessive (one gene from each parent), often no other family members appear to be affected. There is a 25 percent chance of the trait occurring in other siblings.
— If this gene trait is dominant (a gene from either parent), the disease often occurs in other family members. There is a 50 percent chance of the trait occurring in other siblings.
MtDNA (DNA contained in the mitochondria) inheritance.

— There is a 100 percent chance of the trait occurring in other siblings, since all mitochondria are inherited from the mother, although symptoms might be either more or less severe.
Combination of mtDNA and nDNA defects:

— Relationship between nDNA and mtDNA and their correlation in mitochondrial formation is unknown
Random occurrences

— Diseases specifically from deletions of large parts of the mitochondrial DNA molecule are usually sporadic without affecting other family members disease

8. What is Alpers?
Alpers’ Syndrome is a disease of the brain and liver. There are 3 classical symptoms of Alpers’ Syndrome. These are: 1) seizures that are very difficult to treat and have a focal component, 2) episodic psychomotor regression or dementia (loss of developmental milestones, often associated with common childhood infections),
3) liver disease. The children are born and develop normally for a period of time in virtually every case. Symptoms begin between the first few weeks of life and about 25 years of age. Two-thirds of the cases begin to show symptoms of seizures, or episodic loss of developmental milestones, within the first 2 years of life. The liver disease is often subclinical in the early stages of disease, but can appear at any time as acute liver failure.

Alpers’ Syndrome is a recessive genetic disease with a frequency of about 1:250,000 live births. Many cases die before an accurate diagnosis is made, so the true frequency is still an estimate. Alpers is caused by inheriting two copies of the POLG gene that are dysfunctional. These are called mutant copies. The function of the POLG gene is to copy mitochondrial DNA. In Alpers’ Syndrome, POLG is defective, so after a period of time, the amount of mitochondrial DNA in the cell falls below a critical threshold of about 35% of normal. When this happens, the mitochondria become sick, and begin to misfire. This leads to the brain and liver disease of classical Alpers’ Syndrome.

Alpers Syndrome—A Summary for Families
Robert K. Naviaux, MD, PhD

Information provided is intended for educational purposes only and should not be construed as advising or diagnosing or treatment of this or any other medical condition.

Copyright © 2008 Hailey's Wish | Home | Legal Notice | Contact

What They Think Brennan Had

Here's a lovely scientific description of the disease they assumed my baby had. They never did any genetic testing(esp back in 1995)because of the cost.

All Databases PubMed Nucleotide Protein Genome Structure PMC OMIM

#203700 GeneTests, Links

Alternative titles; symbols

Gene map locus 15q25


A number sign (#) is used with this entry because Alpers syndrome can be caused by mutation in the nuclear gene encoding mitochondrial DNA polymerase gamma (POLG; 174763).


Alpers syndrome is usually characterized by a clinical triad of psychomotor retardation, intractable epilepsy, and liver failure in infants and young children. Definitive diagnosis is shown by postmortem examination of the brain and liver (Harding et al., 1995).


The illness usually begins in early life with convulsions. A progressive neurologic disorder characterized by spasticity, myoclonus, and dementia ensues. Status epilepticus is often the terminating development.

Bernard Alpers (1931) described the neuropathology and clinical features in a 4-month-old girl with a one-month illness characterized by intractable generalized seizures. He termed the disorder 'diffuse progressive degeneration of the gray matter of the cerebrum.' Ford et al. (1951) described a brother and sister with a similar disorder. (See myoclonic epilepsy (254800) for reference to the same cases reported by Morse.) Familial cases were also reported by Palinsky et al. (1954) and Christensen and Hojgaard (1964).

Alberca-Serrano et al. (1965) reported a family in which 4 of 6 sibs were affected with spastic diplegia due to anoxic encephalopathy, which they termed 'Alpers' syndrome. The parents were unrelated. Several relatives of the father may have had the same disorder. All affected members had reacted to infections with violent convulsions. The authors suggested that this represented a familial susceptibility and that the cerebral damage was secondary to anoxia.

Blackwood et al. (1963) described 2 sibs in whom diffuse cerebral degeneration (Alpers disease) was associated with cirrhosis of the liver. Wefring and Lamvik (1967) described brother and sister who developed convulsions at ages 11 and 14 months, followed by progressive hypotonia, dementia and jaundice 4 and 2 weeks before death at the ages of 15 and 20 months. In addition to the typical findings of Alpers disease, the liver showed extensive atrophy with fibrosis, inflammation and bile duct proliferation. The diagnosis was made at autopsy.

Sandbank and Lerman (1972) reported 3 sibs with Alpers disease, characterized by progressive mental retardation, seizures, rigidity, and degeneration of the cerebral cortex. Neuropathologic examination showed disorganization of the cerebral cortex with neuronal loss and astroglial proliferation. There were abnormal mitochondria of variable sizes, some with electron dense inclusions. The authors suggested autosomal recessive inheritance.

Huttenlocher et al. (1976) reported 2 sibships with 2 affected children in each. Clinical features included early onset (average 2 years) of delayed motor development, vomiting, multifocal seizures, status epilepticus, stupor, hypotonia, paralysis, increased CSF protein, and later onset of hepatic disease. Intermittent, unexplained fever occurred frequently. None of the children survived beyond age 3 years. Pathologic examination showed degeneration of the cerebral gray matter with loss of neurons and reactive astrocytosis in the brain and fatty accumulation and cirrhosis in the liver. The authors rejected the idea of anoxic encephalopathy and suggested that the syndrome was a familial disorder with autosomal recessive inheritance. Huttenlocher et al. (1976) noted that hepatic involvement was absent in some cases reported earlier, including the case reported by Alpers (1931).

Harding (1990) reviewed the clinical, neurologic, electrophysiologic, and histopathologic features of Alpers syndrome in 32 patients. Birth was usually normal, with some developmental delay in infancy, often with hypotonia and bouts of vomiting. The seizure disorder usually had an abrupt onset and although clinical signs of liver disease often appeared later, biochemical evidence of liver disease was sometimes present before the onset of seizures. EEG and visual evoked potentials were abnormal. Most patients died before the age of 3 years. Less frequently, late presentation occurred, even up to 25 years of age. Some patients also had visual disturbances. Liver pathologic findings, including fatty changes, abnormal bile duct architecture, and fibrosis, were unrelated to anticonvulsant therapy. Neuropathology showed severe cortical neurodegeneration and astrocytosis. In 12 of the 26 families in their series, 2 or 3 sibs were affected, including one pair of twins.

Frydman et al. (1993) reported the cases of 8 patients from 2 families. Onset in the first family was prenatal; in the 4 patients who were examined, severe microcephaly, intrauterine growth retardation, and typical manifestations of fetal akinesia, including retrognathia, joint limitations, and chest deformity, were found. The second family presented with an early infantile form. All of the affected offspring had micrognathia and 1 had findings of fetal akinesia, comparable to those seen in the other family. Microcephaly was mild at birth and progressed with age. Refractory neonatal convulsions, swallowing difficulties, and pneumonia complicated the clinical course of patients in both families, and all of the infants died before age 20 months. Comprehensive biochemical and metabolic studies in both families yielded normal results, and the diagnosis was supported by demonstration of extensive progressive brain atrophy on computerized tomography and typical histologic findings; for example, the parietal cortex showed spongy state with focally accentuated severe loss of neurons. The cerebellar cortex showed severe loss of almost all granular cells and persistent Purkinje cells. Anomalies of dendritic arborization were also seen. Both families were of Israeli Arab ethnicity and the parents were first cousins in both cases.

Harding et al. (1995) reported the unusual cases of 2 unrelated girls, aged 17 and 18, with a progressive encephalopathy, visual signs and symptoms, multiple types of drug-resistant seizures, and liver failure. Brain imaging showed lesions in the occipital lobe, and EEG showed slow waves with polyspikes. Both patients had a rapid degenerative course and died within 8 months of onset.


Cases with a disturbance in pyruvate metabolism and NADH oxidation (10,9:Gabreels et al., 1981, 1984) have been described.

In a patient with mtDNA depletion and Alpers syndrome, Naviaux et al. (1999) found global reduction in respiratory chain complex I, II/III, and IV activity and deficiency of mitochondrial DNA polymerase gamma activity.

Gauthier-Villars et al. (2001) confirmed the mitochondrial respiratory chain abnormalities in the liver of 4 unrelated patients with Alpers syndrome. One patient had a complex I deficiency, another a complex IV deficiency, and 2 had a combined deficiency of complexes I and IV.


Naviaux and Nguyen (2004) reported 3 patients with Alpers syndrome who were homozygous for a mutation (E873X; 174763.0008) in the POLG gene. They later published a correction (Naviaux and Nguyen, 2005) stating that 2 affected patients from 1 family with Alpers syndrome were compound heterozygous for 2 mutations in the POLG gene: E873X and A467T (174763.0002). Naviaux and Nguyen (2005) stated that the existence of a common 4-bp insertion in the POLG gene yielded the incorrect initial results. The clinical features of the family had been described by Naviaux et al. (1999).

In 4 patients with Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene (174763.0006 and 174763.0013). Liver biopsies from 3 patients showed mitochondrial DNA depletion ranging from 87 to 94%, and all 4 patients showed decreased activity of mtDNA-encoded respiratory chain complexes.

Ferrari et al. (2005) identified mutations in the POLG gene in 8 patients with Alpers syndrome.


Nguyen et al. (2005) reported a child with Alpers syndrome who was homozygous for the A467T mutation. Unlike other children with the disorder, he showed late-onset at age 8.5 years and death by age 9 years.


As noted by Harding (1990) in a review of Alpers syndrome, there was much confusion in the past regarding the nosology, pathogenesis, and diagnosis of the disease. Some reported cases seemed to be caused by anoxia at birth or illness, whereas others were familial with normal births. Cerebral damage was also thought to be a result of intractable seizures or hepatic toxicity, and hepatic damage was believed in some cases to be caused by anticonvulsive drugs.


1. Alberca-Serrano, R.; Fabiani, F.; Deneve, V.; Macken, J. :
Familial spastic diplegia due to anoxic encephalopathy (Alpers). A contribution to the study of vascular fragilities of the nervous system of genetic type. J. Neurol. Sci. 2: 419-433, 1965.
PubMed ID : 5878525

2. Alpers, B. J. :
Diffuse progressive degeneration of gray matter of cerebrum. Arch. Neurol. Psychiat. 25: 469-505, 1931.

3. Blackwood, W.; Buxton, P. H.; Cumings, J. N.; Robertson, D. J.; Tucker, S. M. :
Diffuse cerebral degeneration in infancy (Alpers' disease). Arch. Dis. Child. 38: 193-204, 1963.

4. Christensen, E.; Hojgaard, K. :
Poliodystrophia cerebri progressiva infantilis. Acta Neurol. Scand. 40: 21-40, 1964.
PubMed ID : 14108415

5. Davidzon, G.; Mancuso, M.; Ferraris, S.; Quinzii, C.; Hirano, M.; Peters, H. L.; Kirby, D.; Thorburn, D. R.; DiMauro, S. :
POLG mutations and Alpers syndrome. Ann. Neurol. 57: 921-924, 2005.
PubMed ID : 15929042

6. Ferrari, G.; Lamantea, E.; Donati, A.; Filosto, M.; Briem, E.; Carrara, F.; Parini, R.; Simonati, A.; Santer, R.; Zeviani, M. :
Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gamma A. Brain 128: 723-731, 2005.
PubMed ID : 15689359

7. Ford, F. R.; Livingston, S.; Pryles, C. V. :
Familial degeneration of the cerebral gray matter in childhood with convulsions, myoclonus, spasticity, cerebral ataxia, choreoathetosis, dementia, and death in status epilepticus. Differentiation of infantile and juvenile types. J. Pediat. 39: 33-43, 1951.
PubMed ID : 14851183

8. Frydman, M.; Jager-Roman, E.; de Vries, L.; Stoltenburg-Didinger, G.; Nussinovitch, M.; Sirota, L. :
Alpers progressive infantile neuronal poliodystrophy: an acute neonatal form with findings of the fetal akinesia syndrome. Am. J. Med. Genet. 47: 31-36, 1993.
PubMed ID : 8368248

9. Gabreels, F. J.; Prick, M. J.; Trijbels, J. M.; Renier, W. O.; Jaspar, H. H.; Janssen, A. J.; Slooff, J. L. :
Defects in citric acid cycle and the electron transport chain in progressive poliodystrophy. Acta Neurol. Scand. 70: 145-154, 1984.
PubMed ID : 6439001

10. Gabreels, F. J. M.; Prick, M. J. J.; Renier, W. O.; Willems, J. L.; Trijbels, J. M. F.; Ter Laak, H. J.; Jaspar, H. H. J.; Slooff, J. L.; Van Haelst, U. J. G. M.; Sengers, R. C. A. :
Progressive infantile poliodystrophy (Alpers' disease) associated with disturbed NADH oxidation, lipid myopathy and abnormal muscle mitochondria.In: Busch, H. F. M.; Jennekens, F. G. I.; Scholte, H. R. : Mitochondria and Muscular Diseases. Beetsterzwaag, The Netherlands: Mefar (pub.) 1981. Pp. 165-171.

11. Gauthier-Villars, M.; Landrieu, P.; Cormier-Daire, V.; Jacquemin, E.; Chretien, D.; Rotig, A.; Rustin, P.; Munnich, A.; de Lonlay, P. :
Respiratory chain deficiency in Alpers syndrome. Neuropediatrics 32: 150-152, 2001.
PubMed ID : 11521212

12. Harding, B. N. :
Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): a personal review. J. Child Neurol. 5: 273-287, 1990.
PubMed ID : 2246481

13. Harding, B. N.; Alsanjari, N.; Smith, S. J. M.; Wiles, C. M.; Thrush, D.; Miller, D. H.; Scaravilli, F.; Harding, A. E. :
Progressive neuronal degeneration of childhood with liver disease (Alpers' disease) presenting in young adults. J. Neurol. Neurosurg. Psychiat. 58: 320-325, 1995.
PubMed ID : 7897414

14. Huttenlocher, P. R.; Solitare, G. B.; Adams, G. :
Infantile diffuse cerebral degeneration with hepatic cirrhosis. Arch. Neurol. 33: 186-192, 1976.
PubMed ID : 1252162

15. Naviaux, R. K.; Nguyen, K. V. :
POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. (Letter) Ann. Neurol. 58: 491 only, 2005.
PubMed ID : 16130100

16. Naviaux, R. K.; Nguyen, K. V. :
POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. Ann. Neurol. 55: 706-712, 2004.
PubMed ID : 15122711

17. Naviaux, R. K.; Nyhan, W. L.; Barshop, B. A.; Poulton, J.; Markusic, D.; Karpinski, N. C.; Haas, R. H. :
Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome. Ann. Neurol. 45: 54-58, 1999.
PubMed ID : 9894877

18. Nguyen, K. V.; Ostergaard, E.; Ravn, S. H.; Balslev, T.; Danielsen, E. R.; Vardag, A.; McKiernan, P. J.; Gray, G.; Naviaux, R. K. :
POLG mutations in Alpers syndrome. Neurology 65: 1493-1495, 2005.
PubMed ID : 16177225

19. Palinsky, M.; Kozinn, P. J.; Zahtz, H. :
Acute familial infantile heredodegenerative disorder of the central nervous system. J. Pediat. 45: 538-545, 1954.
PubMed ID : 13212595

20. Sandbank, U.; Lerman, P. :
Progressive cerebral poliodystrophy--Alpers' disease: disorganized giant neuronal mitochondria on electron microscopy. J. Neurol. Neurosurg. Psychiat. 35: 749-755, 1972.
PubMed ID : 4647849

21. Wefring, K. W.; Lamvik, J. O. :
Familial progressive poliodystrophy with cirrhosis of the liver. Acta Paediat. Scand. 56: 295-300, 1967.
PubMed ID : 6033104


Cassandra L. Kniffin - updated : 2/15/2007
Cassandra L. Kniffin - updated : 10/13/2005
Cassandra L. Kniffin - updated : 8/31/2005
Cassandra L. Kniffin - reorganized : 8/15/2003
Victor A. McKusick - updated : 8/8/2003


Victor A. McKusick : 6/2/1986


wwang : 2/21/2007
ckniffin : 2/15/2007
carol : 11/15/2005
ckniffin : 10/13/2005
wwang : 9/6/2005
ckniffin : 8/31/2005
tkritzer : 8/13/2004
ckniffin : 8/4/2004
ckniffin : 7/12/2004
mgross : 3/17/2004
carol : 8/15/2003
ckniffin : 8/15/2003
carol : 8/8/2003
alopez : 6/10/1997
mimadm : 11/12/1995
terry : 4/21/1994
warfield : 3/7/1994
carol : 9/1/1993
supermim : 3/16/1992
supermim : 3/20/1990

Copyright © 1966-2008 Johns Hopkins University

Write to the Help Desk
Department of Health & Human Services
Privacy Statement | Freedom of Information Act | Disclaimer

Friday, March 28, 2008

Dear Brennan Who Never Got the Opportunity to Grow up

My dearest son,

I'm 46. It's been 12 years since you were ripped from our family by a bizarrely rare incredibly odd disease. You lived 10 months and 11 days. I have no idea how you comprehended your small time with us. In spite of pain and guilt and extreme frustration; I am delighted I got to love and nurture and care for you during your short life.

I was ecstatic when I learned we were pregnant with you. I had a miscarriage a few months before that was traumatic in a physical manner but not so devastating emotionally. This time I got to see the baby I miscarried, so there was a final closure to the event. My attitude was OK, God felt there was an inborn error that meant that baby could not survive.

Your father and I waited 6 weeks and tried again. We were thrilled to be trying to create you with the help of God. It never mattered if you were female or male, we just wanted a healthy infant to love, to show the product of our love, and to enjoy parenting. We relished raising your brothers at 6 and 4. They were more of a joy than work and they were loving, snuggly, loving children. I was fabulously happy being a full time mother and wife.

So when we got the news you were coming we were happy, slightly leery but happy. The pregnancy was different from my others. I chose a midwife. I didn't have a happy energized pregnancy with you as I did with Riley. I was more tired with you being 32 at the time. I had a child in 1st grade and one in preschool plus soccer for both.

My hair went flat ad lifeless for the first time ever-thanks. I had very little nausea or headaches as I had suffered through with your brothers. I was more tired.
Kinda klutzy as I fell through the stairs at Charmaine's. Nice bruises on my arms and knees

I fell another time in the middle of the night when Ry went pee in his bathroom but it was clear and I did not see it. WHAMMO went my 7 months pregnant body. I twisted so the brunt of the fall affected my back and upper side. I did need to call your dad to help me get up. I was fairly unwieldy by then (like a beached whale).

There was the exciting(yeah right) time Riley was sleeping bed with me and you inside me and he threw up all over my back and hair. Once again, I screamed for Daddy for help. You, I and Ry took a nice warm shower and Daddy did the laundry. He was such a good daddy/husband.

I would lie in bed and feel you move. You never matched the level of the frenzy of your brothers but you did move. You were breech from early on. Your hard head was under my ribs, your ankles tickled your ears and you little butt was wedged firmly down in the pelvis. You would get the hiccups and I would grin internally because I know this meant you alive and most likely normal.

Your time inside me was a gift. It's a gift to create a life. I can not describe the radiance and peace I felt when you were inside me. You were our child but again, a child is a gift, leaving the future to be unknown. We were okay with that risk. After 2 healthy boys and 2 miscarriages, we understood(or we thought) we understood the risk to love outweighs the fears.

Friday, March 14, 2008

Pop Up Feelings

Because of our move a whole 11 blocks south, I've been sorting and packing in the last 10 days or so.

I came upon my breast pump accessories, totally unexpected, and I lost it. I wept for over 30 minutes.

I wept for a life cut short.

I wept for a future denied.

I wept for the sweet boy I never got to see turn into a toddler let alone a teen.

Brennan Reed would have been 13 on March 22.

I wept for the suffering my innocent infant had to bear.

I wept, selfishly for me. For that family picture of all three boys in baseball uniforms lined up tallest to smallest. The picture that only existed in my mind.

I wept for the sadness I carry with me everywhere, even if it invisible to others.

I did not feel better or worse after I stopped crying. I just felt very much alone.

I miss him~always.