Saturday, March 29, 2008

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.


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ALPERS DIFFUSE DEGENERATION OF CEREBRAL GRAY MATTER WITH HEPATIC CIRRHOSIS

Alternative titles; symbols

ALPERS PROGRESSIVE INFANTILE POLIODYSTROPHY
ALPERS SYNDROME
ALPERS-HUTTENLOCHER SYNDROME
NEURONAL DEGENERATION OF CHILDHOOD WITH LIVER DISEASE, PROGRESSIVE; PNDC
Gene map locus 15q25


TEXT

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).


DESCRIPTION

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).


CLINICAL FEATURES

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.


OTHER FEATURES

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.


MOLECULAR GENETICS

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.


GENOTYPE/PHENOTYPE CORRELATIONS

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.


HISTORY

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.


REFERENCES

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


CONTRIBUTORS

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



CREATION DATE

Victor A. McKusick : 6/2/1986



EDIT HISTORY

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


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1 comment:

Mirabel said...

Keep up the good work.