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Clinical History

A 6 year old male born to non consanguineous parents presented with nephrotic syndrome. He also had persistent gastrointestinal symptoms (vomiting and post prandial diarrhoea) from 12 months of age and recurrent asymptomatic neutropenia from 24 months of age which progressed to pancytopenia. His upper and lower GI endoscopies were normal.  He had a normal bone marrow and karyotype.

Urinary 24 hour proteinuria was documented as 3.2 g, with hypoalbuminemia, hypercholesterolemia and normal renal function. All serologies were negative and he did not have any family history of renal disease. 

 

Kidney Biopsy Findings: 

Figure 1. Glomeruli appear non – proliferative. Hematoxylin Eosin stain

Figure 2.Interstitial chronic inflammation is noted with a small collection of macrophages. Hematoxylin Eosin stain 

 

Figure 3. There is evidence of diffuse cytoplasmic podocytic vacuolization. Hematoxylin Eosin stain 

Figure 4. Transmission electron microscopic images demonstrate numerous ‘myelin figures’ and ‘zebra bodies’ within the podocytic cytoplasm

FINAL DIAGNOSIS

Nonproliferative glomerular morphology with histological and ultrastructural features of a Renal Lipidoses suspicious for Fabry Nephropathy 

ON FURTHER EVALUATION

Leucocyte alpha galactosidase activity was low (< 0.01 U/L, normal 0.07-0.45 U/L and clinical exome sequencing demonstrated hemizygous missense variation in exon 3 of GLA gene ( c.440G>A, p. Gly147Glu) deemed ‘Likely Pathogenic’. This confirmed the diagnosis of Fabry disease. 

DISCUSSION

Fabry disease is a lysosomal storage disease first described in 1898 by Johannes Fabry and William Anderson. It is the second most frequent lysosomal storage disease after Gaucher disease. 

It occurs due to mutations in the GLA gene resulting in deficiency of the enzyme alpha-galactosidase A. This results in accumulation of globotriaosylceramide (GL3), in the form of intralysosomal inclusions.  

Fabry disease follows a recessive X-linked pattern of inheritance. Classically, it affects hemizygous males with no residual α-galactosidase A activity. Clinical signs and symptoms vary widely in heterozygous females. This phenotypic heterogeneity is due to random X inactivation (Lyonization).

Classic features include neuropathy, angiokeratoma and Fabry cataract. Gastrointestinal symptoms such as abdominal pain and diarrhea may be found, as was noted in this case. Renal involvement in the form of proteinuria and renal dysfunction occurs due to toxicity of the accumulated globotriasylceramide. 11-23% patients present with nephrotic range proteinuria.

On light microscopy, glomeruli show vacuolization of podocytes, mesangial or endothelial cells, and sometimes, glomerular parietal epithelial cells.  Vacuolization is also present in epithelial cells of distal tubules, Henle loops, and collecting ducts. The involvement of proximal tubular epithelial cells is uncommon. Ultrastructural analysis shows intracellular osmiophilic, lamellated membrane structures with a concentric pattern called myelin bodies or with elongated stripes called zebra bodies.

Early initiation of enzyme replacement therapy results in better long-term outcome.

Differential diagnoses include other Renal lipidoses (Niemann Pick disease, Hurler disease etc) as well as iatrogenic lysosomal inhibitor usage (chloroquine, hydroxychloroquine, amiodarone). Therefore definitive diagnosis requires measurement of enzyme levels and demonstration of the mutation in GLA gene.

               

REFERENCES

1. Colpart P, Félix S. Fabry Nephropathy. Arch Pathol Lab Med. 2017 Aug;141(8):1127-1131. doi: 10.5858/arpa.2016-0418-RS. PMID: 28745569.
2. Del Pino M, Andrés A, Bernabéu AÁ, de Juan-Rivera J, Fernández E, de Dios García Díaz J, Hernández D, Luño J, Fernández IM, Paniagua J, Posada de la Paz M, Rodríguez-Pérez JC, Santamaría R, Torra R, Ambros JT, Vidau P, Torregrosa JV. Fabry Nephropathy: An Evidence-Based Narrative Review. Kidney Blood Press Res. 2018;43(2):406-421. doi: 10.1159/000488121. Epub 2018 Mar 16. PMID: 29558749.
3. Jaurretche S, Antongiovanni N, Perretta F. Fabry nephropathy. Role of nephrologist and clinical variables associated with the diagnosis. Nefrologia (Engl Ed). 2019 May-Jun;39(3):294-300. English, Spanish. doi: 10.1016/j.nefro.2018.10.017. Epub 2019 Mar 16. PMID: 30890379.