OOA (Old Order Amish)

Inheritance: autosomal recessive
Genes: NPHP3

Nephronophthisis
Amish polycystic kidney disease
Neonatal kidney disease

Respiratory distress
Lethal neonatal kidney disease
Polycystic kidneys
Multicystic kidneys

Polycystic Kidney Disease

Clinical Characteristics

General description (for patients):

This is an aggressive, lethal kidney disease usually manifest at birth as respiratory distress.  So far, all patients have come from the Northern Indiana community.  Most infants are born prematurely after 34-36 weeks of pregnancies and weigh less than 5 lbs although rare infants are carried to term and can weigh 7 or more lbs.  Maternal weight gain is low and “dry births” are common. Some are born without a bladder.  Most are noted to have low-set ears.  Breech deliveries are common.  Breathing difficulties are always present to some extent at birth and poor lung devlelopment is the primary cause of death, usually within a day or two.  Poor kidney function also contributes with no urine production noted in some infants.  Heart defects, sometimes severe, are present in some infants.

Medical aspects: 

This is a lethal, neonatal form of nephronophthisis.  Gestation is often shortened to 34-36 weeks, and birth weight is usually under five lbs. Maternal weight gain is low and oligohydramnios is often noted.  Breech presentation is common. Virtually all are noted to have respiratory distress immediately, and death in the first hours or at most a few days is inevitable.  The ears are often low-set and posteriorly rotated. Heart defects such as VSD, ASD and even situs inversus may be present.  All infants have polycystic kidneys and the bladder may be absent.  So far, none have had documented polycystic disease of the liver.  X-rays of the lungs in several cases have shown collapsed, small, and sometimes single lobes. No autopsy information is available.

Genetics:

This is an autosomal recessive disorder so far found only among the Northern Indiana Amish. It is due to a nonsense mutation in the NPHP3 gene located on chromosome 3. The normal sequence is altered at position 2104 by a cytosine to thymine substitution in exon 15.  All parents were heterozygous for this mutation and the single infant available for testing was homozygous.

Treatment:

No treatment is known.  The absence or near absence of kidney function together with the pulmonary maldevelopment is uniformly fatal.

Prognosis:

Lethal.

Ancillary treatments and support:

None known.  Less severely affected cases may live for several days or weeks with life support.

Specialists and specialty centers:

Renal and pulmonary specialists should be consulted.

References:

Simpson, M.A., Cross, H.E., Cross, L., Helmuth, M., Crosby, A.H.:  Lethal polycystic kidney disease in Amish neonates caused by homozygous nonsense mutation of NPHP3.  Amer. J. Kidney Dis.  Amer. J. Kidney Dis. Mar 19, 2009, Epub: PubMed: 19303681

Olbrich, H., Fliegauf, M., Hoefele, J., Kispert, A., Otto, E., Volz, A., Wolf, M.T., Sasmaz, G., Trauer, U., Reinhardt, R., Sudbrak, R., Antignac, C., Gretz, N., Walz, G., Schermer, B. Benzing, T., Hildebrandt, F., Omran. H.:  Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis.  Nat. Genet. 34: 455-459, 2003. PubMed ID: 12872122

Bergmann, C., Fliegauf, M., Bruchle, N.O., Frank, V., Olrich, H., Kirschner, J., Schermer, b., Schmedding, I, Kispert, A., Kranzlin, B., Nurnberg, G., Becker, C., Grimm, T, Girschick, G., Lynch, S.A., Kelehan, P., Senderek, J., Neuhaus, T.J., Stallmach, T., Zentfraf, H., Nurnber, P., Gretz, N., Lo, C., Lienkeamp, S., Schater, T., Walz, G., Benzing, T., Zerres, K., Omran, H.:  Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Am. J. Hum. Genet. 82: 959-970, 2008. PubMed ID: 18371931

Resources:

PKD Foundation