Neurology -- Correspondence for Goizet et al., 58 (6) 962-965

HOME

HELP

FEEDBACK

SUBSCRIPTIONS

Correspondence published:

Reply to Letter to the Editor: Cyril Goizet, Didier Lacombe (17 July 2002)

Progressive bulbospinal amyotrophy in Triple A syndrome with AAAS gene mutation: Mamede deCarvalho, Henry Houlden (17 July 2002)

Reply to Letter to the Editor 17 July 2002

Cyril Goizet
Hopital Pellegrin-Enfants Bordeaux France,
Didier Lacombe
Send Correspondence to journal:
Re: Reply to Letter to the Editor

cyril.goizet{at}chu-bordeaux.fr Cyril Goizet, et al.

We thank Drs. de Carvalho and Houlden for their interest concerning our adult patient with Allgrove (Triple A) syndrome and neurological features.[5] We previously reported an adult patient with Triple A syndrome and prominent bulbospinal amyotrophy associated with a mutation identified in the AAAS gene.[1] Although we mentioned that motor neuron involvement could occur in Triple A syndrome, [6] we must apologize to the authors for not including their paper in our references.
The case reported by Bentes et al.[3] exhibited features of bulbospinal amyotrophy on clinical examination and EMG, with in addition a predominantly motor peripheral neuropathy.[3] The evolution of this case was atypical with regard to the late recognition of alacrima and compensated adrenal insufficiency. A homozygous missense mutation V313A was recently identified in the AAAS gene.[4] Drs. de Carvalho and Houlden describe additional cases with molecularly proven Triple A syndrome and neurological presentation.[5] All manifested distal amyotrophy and predominant motor neuropathy on nerve conduction studies, thus confirming that peripheral neuropathy is a significant component of Triple A syndrome.[6] The high frequency of amyotrophy led us to propose the eponym of 5A syndrome.[1] Increased tone, brisk reflexes and Babinski signs were reported in several cases, thereby arguing for an underestimation of CNS involvement in Triple A syndrome. A systematic neurological assessment should be proposed in every affected patient.
As achalasia, alacrima and adrenal insufficiency may result from an autonomic neuropathy, a progressive degenerative process of the entire nervous system has been proposed as the cause of the syndrome.[7] The neurologic involvement may be the first feature to occur in Triple A syndrome. The AAAS gene is widely expressed in fetal and adult tissues, particularly in endocrine and neuroendocrine derivatives and in brain.[2, 8] The function of this gene coding for the ALADIN protein is still unknown. ALADIN contains four WD (trp-asp) repeats and an amino acid triplet Ser- His-Leu in the C-terminal end.[7] Although WD repeats are involved in protein-protein interactions, the topogenic tripeptide has been shown to direct proteins to and into peroxisomes.[9] Various target proteins in different tissues may be involved, leading to different clinical phenotypes. Further molecular and functional studies are needed to better understand the disease.
References:
1. Goizet, C, Cartargi B, Tison F, et al. Progressive bulbospinal amyotrophy in triple A syndrome with AAAS gene mutation. Neurology 2002;58:962-965.
2. Tulio-Pellet A, Salomon R, Hadj-Rabia S, et al. Mutation of a novel WD-repeat protein gene in Allgrove (triple A) syndrome. Nat Gente 2000;26:332-335.
3. Bentes C, Santos-Bento M, de Sa J, Sales Luis ML, de Carvalho M. Allgrove syndrome in adulthood. Muscle Nerve 2001;24:292-296.
4. Houlden H, Smith s, de Carvalho M, et al. Clinical and Genetic characterization of families with Triple A (Allgrove) syndrome. Brain (in press).
5. de Carvalho M, Houlden H Progressive bulbospinal amyotrophy in Triple A syndrome with AAAS gene mutation. Neurology 2002; In press
6. Grant DB, Barnes ND, Dumic M, et al. Neurological and adrenal dysfunction in the adrenal insufficiency/achalasia/alacrima (3A) syndrome. Arch Dis Child 1993;68:779-782.
7. Gazarian M, Cowell CT, Bonney M, Grigor WG. The �4A� syndrome: adrenocortical insufficiency associated with achalasia, alacrima, autonomic and other neurological abnormalities. Eur J Pediatr 1995;154:18- 23.
8. Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet 2001;10:283-290.
9. Gould SJ, Valle D. Peroxisome biogenesis disorders: genetic and cell biology. Trends Genet 2000;16:340-345.

Progressive bulbospinal amyotrophy in Triple A syndrome with AAAS gene mutation 17 July 2002

Mamede deCarvalho
Hospital de Santa Maria Lisboa Portugal,
Henry Houlden
Send Correspondence to journal:
Re: Progressive bulbospinal amyotrophy in Triple A syndrome with AAAS gene mutation

mamedemg{at}mail.telepac.pt Mamede deCarvalho, et al.

Goizet et al. [1] claimed to report the first adult case of Allgrove syndrome (AS) presenting with prominent bulbospinal amyotrophy. This patient had hypoglycemia, hyperpigmentation, mental retardation, and alacrima since childhood. On neurologic examination she showed symmetric four-limb amyotrophy, predominantly distal, upper motor neuron signs, bulbar dysarthria and swallowing difficulties. Sequencing of the patient�s DNA identified a homozygous nonsense mutation at condon 478 in exon 16 of the AAAS gene 1, which have been implied as responsible for this syndrome. [2]
We have previously reported a similar case. [3] Our patient, a man with a past history of achalasia, developed progressive spastic tetraparesis, distal limb atrophy, dysarthria, and dysphagia at 35 years. He had no familial history, and his parents had no consanguinity. A clinical diagnosis of ALS was considered before neurophysiological investigation, which disclosed a polyneuropathy and a prolonged central conduction time on transcranial magnetic stimulation. One year later, he developed dysautonomic symptoms. Laboratory studies confirmed latent adrenal insufficiency. This patient has two previously unidentified homozygous mutations, one that caused the amino acid change valine to alanine at codon 313 and another that causes a deletion of ATAA in the poly a tract (base pairs 1730-1733). [4] The exonic mutation is likely the pathogenic mutation in this family as the deletion is after the stop codon of the triple a gene although mutations that disrupt the poly A tract can be pathogenic by affecting mRNA stability or splicing. [5]
We studied in addition five other families with AS. [4] They had mutations spread throughout the triple A gene in exons 1, 2, 7, 8, 10, 11, 12, 13 and 16. [4] We identified a number of associated cranial nerve abnormalities in these pedigrees including two families who had bilateral hypoglossal nerve palsies and dysarthria. In all there was pes cavus and predominantly distal weakness and wasting in the upper and lower limbs in all families. In the upper limbs this was patchy with marked weakness in an ulnar distribution and wasting of the hypothenar eminence. The tone was generally increased in the upper and lower limbs, reflexes were brisk in the upper limbs but the ankle jerks were lost, plantar reflexes were extensor in one family and equivocal in another. Nerve conduction studies showed predominant motor neuropathy, with selective involvement of ulnar nerves in the upper limbs, but no entrapment of this nerve at elbow. [4]
Our patient had neurologic symptoms before overt autonomic involvement, [3] which makes this case more atypical than the one reported by Goizet et al. [1] We agree with the authors that the possibility of Allgrove syndrome must be borne in our mind even when adult patients presenting with slowly progressive bulbospinal amyotrophy are evaluated.
References:
1) Goizet C, Cartargi B, Tison F, et al. Progressive bulbospinal amyotrophy in triple A syndrome with AAAS gene mutation. Neurology 2002;58:962-965.
2) Tulio-Pellet A, Salomon R, Hadj-Rabia S et al. Mutation of a novel WD-repeat protein gene in Allgrove (triple A) syndrome. Nat Gente 2000;26:332-335.
3) Bentes C, Santos-Bento M, de Sa J, Sales Luis ML, de Carvalho M. Allgrove syndrome in adulthood. Muscle Nerve 2001;24:292-296.
4) Houlden H, Smith S, de Carvalho M, et al. Clinical and Genetic characterization of families with Triple A (Allgrove) syndrome. Brain (in press).
5) Beaudoing E, Freier S, Wyatt JR, Claverie J-M, Gautheret D. Patterns of Variant Polyadenylation Signal Usage in Human Genes. Genome Res 2000;10:1001-1010.